K-Ras modulators

ABSTRACT

Provided herein are the K-Ras inhibitors of the formulae:Also provided are compositions comprising thereof for treating cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national stage entry of PCT Application No.PCT/US18/28593 filed Apr. 20, 2018, which claims the benefit of U.S.Provisional Application No. 62/487,756 filed Apr. 20, 2017, thedisclosure of each of which is incorporated by reference herein in itsentirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

The invention was made with government support under contract no.HHSN261200800001E and grant nos. R35 CA197709 and U01 CA168370 awardedby the National Institutes of Health. The government has certain rightsin the invention.

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED AS AN ASCII FILE

The Sequence Listing written in file 048536-592001WO_ST25.TXT, createdon Apr. 18, 2018, 4,781 bytes, machine format IBM-PC, MS Windowsoperating system, is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

K-Ras is the most frequently mutated oncogene in human cancer. Pastattempts to directly modulate the activity of this enzyme have beenunsuccessful. Ras proteins are small guanine nucleotide-binding proteinsthat act as molecular switches by cycling between active GTP-bound andinactive GDP-bound conformations. The Ras proteins play a critical rolein the regulation of cell proliferation, differentiation, and survival.Dysregulation of the Ras signaling pathway is almost invariablyassociated with disease. Hyper-activating somatic mutations in Ras areamong the most common lesions found in human cancer. Although mutationof any one of the three Ras isoforms (K-Ras, N-Ras, or H-Ras) has beenshown to lead to oncogenic transformation, K-Ras mutations are by farthe most common in human cancer. For example, K-Ras mutations are knownto be often associated with pancreatic, colorectal and non-small-celllung carcinomas. There is a need in the art for effective Ras inhibitorsand anticancer compounds. Disclosed herein are solutions to these andother problems in the art.

BRIEF SUMMARY OF THE INVENTION

Described herein, inter alia, is the use of K-Ras inhibitors (e.g., fortreating cancer).

In an aspect is provided a compound having the formula:

Ring A is an aryl or heteroaryl.

R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B), —NHNR^(1A)R^(1B),—ONR^(1A)R^(1B), —NHC═(O)NHNR^(1A)R^(1B), —NHC(O)NR^(1A)R^(1B),—N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C), —C(O)—OR^(1C),—C(O)NR^(1A)R^(1B), —OR^(1D), —NR^(1A)SO₂R^(1D), —NR^(1A)C(O)R^(1C),—NR^(1A)C(O)OR^(1C), —NR^(1A)OR^(1C), —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl; two adjacent R¹ substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

The symbol z1 is an integer from 0 to 4.

R² is independently hydrogen, —CX² ₃, —CHX² ₂, —CH₂X², —C(O)R^(2A),—C(O)OR^(2A), —C(O)NR^(2A)R^(2B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl.

L¹ is a bond, substituted or unsubstituted alkylene, substituted orunsubstituted cycloalkylene, or

L² is a bond, —O—, —C(O)—, —C(O)O—, —OC(O)—, —S—, —SO—, —S(O)₂—, —NH—,—NHC(O)—, —C(O)NH—, —SO₂NH—, —NHSO₂—, —OC(O)NH—, —NHC(O)O—, —NHC(O)NH—,—C(O)OCH₂—, —CH₂OC(O)—, —C(O)NHCH₂—, —CH₂NHC(O)—, —CH₂NHCH₂—,substituted or unsubstituted alkylene, or substituted or unsubstitutedheteroalkylene.

L³ is a bond, —S(O)₂—, —N(R³)—, —O—, —S—, —C(O)—, —C(O)N(R³)—,—N(R³)C(O)—, —N(R³)C(O)NH—, —NHC(O)N(R³)—, —C(O)O—, —OC(O)—, substitutedor unsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene.

R³ is independently hydrogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —C(O)R^(3A),—C(O)OR^(3A), —C(O)NR^(3A)R^(3B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

L⁴ is a bond, —S(O)₂—, —N(R⁴)—, —O—, —S—, —C(O)—, —C(O)N(R⁴)—,—N(R⁴)C(O)—, —N(R⁴)C(O)NH—, —NHC(O)N(R⁴)—, —C(O)O—, —OC(O)—, substitutedor unsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene.

R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —C(O)R^(4A),—C(O)OR^(4A), —C(O)NR^(4A)R^(4B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R⁵ is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, or E.

E is a histidine binding moiety.

Each R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(3A), R^(3B),R^(4A), and R^(4B) is independently hydrogen, —CX₃, —CN, —COOH, —CONH₂,—CHX₂, —CH₂X, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R^(1A)and R^(1B) substituents bonded to the same nitrogen atom may optionallybe joined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; R^(2A) and R^(2B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R^(3A) and R^(3B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R^(4A) and R^(4B) substituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl.

Each X, X¹, X², X³, and X⁴ is independently —F, —Cl, —Br, or —I.

The symbol n1 is independently an integer from 0 to 4.

The symbols m1 and v1 are independently 1 or 2.

In embodiments, when Ring A is aryl, L¹ is a bond, substituted orunsubstituted alkylene, or substituted or unsubstituted cycloalkylene.

In another aspect is provided a pharmaceutical composition including acompound described herein and a pharmaceutically acceptable excipient.

In another aspect is provided a method of treating cancer in a patientin need of such treatment.

In an aspect is provided a method of reducing the level of activity of aK-Ras protein, the method including contacting the K-Ras protein with acompound described herein.

In another aspect is provided a method of modulating a K-Ras protein,the method including contacting the K-Ras protein with a compounddescribed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. H95 located in G-domain of K-Ras, and sequence comparison of K,N, and HRas at this site. Targeting H95 would affect both splicevariants of KRas, 4A and 4B. The sequences depicted in the figurescorrespond to: FAINNTKSFEDIHHYREQIKRVKD (SEQ ID NO: 1),FAINNTKSFEDIHQYREQIKRVKD (SEQ ID NO:2), and FAINNTKSFADINLYREQIKRVKD(SEQ ID NO:3).

FIG. 2. Dose response experiments identified triazoles 966844 and 966854and phenylacetamide 917105 as strong binders at H95 site of KRas.

FIG. 3. Thermal melting analysis that revealed significant shifts in Tmupon fragment binding identified triazoles 966844 and 966854 andphenylacetamide 917105 as strong binders at H95 site of KRas.

FIG. 4. Select compound structures.

FIG. 5. Tetrafluorophenoxyketone analogues of H95C tethering screenhits.

FIG. 6. Compounds with linker substitutions.

FIG. 7. Electrophilic moiety substitutions.

FIGS. 8A-8F. FNL-0012 causes growth arrest and downregulation of MAPKsignaling in KRas-driven mouse embryonic fibroblasts (MEFs) and inmalignant cell lines. (FIG. 8A) Inhibition of proliferation in KRas4BG12D MEFs after 24 h treatment with FNL-0012; (FIG. 8B) Structures ofFNL-0010 and FNL-0012; (FIG. 8C) Dose-dependent growth arrest in KRas4bG12D MEFs after 45 h treatment with FNL-0012; (FIG. 8D) Decrease in KRasprotein level and MAPK signaling in KRas4b G12D MEFs after 45 h withFNL-0012; (FIG. 8E) Decrease in P-MEK and P-Erk in HupT4 pancreascarcinoma cells after 24 h with FNL-0012, but not with FNL-0010; (FIG.8F) Growth arrest in HupT4 cells treated with FNL-0012 for 24 h.

FIG. 9. MALDI-TOF analysis of KRas4b (1-188) reacted with FNL-0010 andFNL-0012 for 24 h.

FIGS. 10A-10B. FIG. 10A. Structures of FNL-0010, FNL-0012, and FNL-0030.FIG. 10B. MALDI-TOF analysis of KRas H95C (1-169) reacted with FNL-0010,FNL-0012, and FNL-0030 for 24 h.

FIGS. 11A-11C. FIG. 11A. Compound FNL-0012 (12), FNL-0036 (36), FNL-0037(37), FNL-0038 (38). FIG. 11B. Growth arrest in HupT4 treated withFNL-0012, but not with control compounds (structures depicted in FIG.11A). Images were taken at 72 h time point. FIG. 11C. HupT4 were treatedwith DMSO (D), left untreated (−), or 40 μM compound FNL-0012 (12),FNL-0036 (36), FNL-0037 (37), FNL-0038 (38). Decrease in MAPK signalingafter 24 h, and decrease in KRas protein level and MAPK signaling after72 h of treatment with FNL-0012, but not the controls.

FIGS. 12A-12B. FIG. 12A: Growth arrest caused by treatment with FNL-0012in KRas4b G12D MEFs only, not in BRAF V600E MEFs. FIG. 12B: Decrease inMEK phosphorylation in KRas MEFs (G12D or G12D/H95Q), not in BRAF V600EMEFs.

FIG. 13. Dose-dependent growth arrest and downregulation of MAPKsignaling in HupT4 cells treated with compound FNL-0012.

FIGS. 14A-14C. FIG. 14A: Structures of a single enantiomer derivativesof compound FNL-0012: FNL-0042 (S) or FNL-0044 (R), and derivatives ofFNL-0030: FNL-0043 (S) and FNL-0045 (R). FIG. 14B: MALDI-TOF MS analysisindicated significantly higher level of covalent labeling of KRAS4b H95Cby R enantiomer. FIG. 14C: HupT4 cells were treated with singleenantiomer derivatives at 40 μM for 48 h. In both cases, the Renantiomer caused growth arrest, with S isomer being inactive.

FIGS. 15A-15B: FIG. 15A depicts a series of analogues of FNL-0045. FIG.15B depicts graphs of cell proliferation experiments with KRAS4b G12D,KRAS4b G12V, HRas WT/P53-, and SUIT-2, for the compounds FNL-0088 (left)and FNL-0090 (right).

I. DEFINITIONS

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchedcarbon chain (or carbon), or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include mono-, di- andmultivalent radicals. The alkyl may include a designated number ofcarbons (e.g., C₁-C₁₀ means one to ten carbons). Alkyl is an uncyclizedchain. Examples of saturated hydrocarbon radicals include, but are notlimited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. Examples of unsaturated alkyl groups include, but are not limitedto, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. An alkoxy is an alkylattached to the remainder of the molecule via an oxygen linker (—O—). Analkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynylmoiety. An alkyl moiety may be fully saturated. An alkenyl may includemore than one double bond and/or one or more triple bonds in addition tothe one or more double bonds. An alkynyl may include more than onetriple bond and/or one or more double bonds in addition to the one ormore triple bonds.

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred herein. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms. The term “alkenylene,” byitself or as part of another substituent, means, unless otherwisestated, a divalent radical derived from an alkene.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, including at least one carbon atom and at leastone heteroatom (e.g., selected from the group consisting of O, N, P, Si,and S, and wherein the nitrogen and sulfur atoms may optionally beoxidized, and the nitrogen heteroatom may optionally be quaternized).The heteroatom(s) (e.g., O, N, P, S, B, As, or Si) may be placed at anyinterior position of the heteroalkyl group or at the position at whichthe alkyl group is attached to the remainder of the molecule.Heteroalkyl is an uncyclized chain. Examples include, but are notlimited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—S—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and—CN. Up to two or three heteroatoms may be consecutive, such as, forexample, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃.

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl andheteroalkyl are not aromatic. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means adivalent radical derived from a cycloalkyl and heterocycloalkyl,respectively.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. In some embodiments, fused ring aryl includes two ormore rings fused together wherein at least one of the fused rings is anaromatic hydrocarbon ring, and at least one ring is a non-aromatic ringcomprising a heteroatom, for example

are each considered aryl as defined herein. The term “heteroaryl” refersto aryl groups (or rings) that contain at least one heteroatom such asN, O, or S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. Thus, theterm “heteroaryl” includes fused ring heteroaryl groups (i.e., multiplerings fused together wherein at least one of the fused rings is aheteroaromatic ring), for example,

are considered heteroaryl. A 5,6-fused ring heteroarylene refers to tworings fused together, wherein one ring has 5 members and the other ringhas 6 members, and wherein at least one ring is a heteroaryl ring.Likewise, a 6,6-fused ring heteroarylene refers to two rings fusedtogether, wherein one ring has 6 members and the other ring has 6members, and wherein at least one ring is a heteroaryl ring. And a6,5-fused ring heteroarylene refers to two rings fused together, whereinone ring has 6 members and the other ring has 5 members, and wherein atleast one ring is a heteroaryl ring. A heteroaryl group can be attachedto the remainder of the molecule through a carbon or heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl,naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl,imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl,thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl,benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl,isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl,4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl. Substituents for each of the above noted aryl and heteroarylring systems are selected from the group of acceptable substituentsdescribed below. An “arylene” and a “heteroarylene,” alone or as part ofanother substituent, mean a divalent radical derived from an aryl andheteroaryl, respectively. A heteroaryl group substituent may be —O—bonded to a ring heteroatom nitrogen.

Spirocyclic rings are two or more rings wherein adjacent rings areattached through a single atom. The individual rings within spirocyclicrings may be identical or different. Individual rings in spirocyclicrings may be substituted or unsubstituted and may have differentsubstituents from other individual rings within a set of spirocyclicrings. Possible substituents for individual rings within spirocyclicrings are the possible substituents for the same ring when not part ofspirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkylrings). Spirocyclic rings may be substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkylene, substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheterocycloalkylene and individual rings within a spirocyclic ring groupmay be any of the immediately previous list, including having all ringsof one type (e.g. all rings being substituted heterocycloalkylenewherein each ring may be the same or different substitutedheterocycloalkylene). When referring to a spirocyclic ring system,heterocyclic spirocyclic rings means a spirocyclic rings wherein atleast one ring is a heterocyclic ring and wherein each ring may be adifferent ring. When referring to a spirocyclic ring system, substitutedspirocyclic rings means that at least one ring is substituted and eachsubstituent may optionally be different.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylarylene” as an arylene moiety covalently bonded to analkylene moiety (also referred to herein as an alkylene linker). Inembodiments, the alkylarylene group has the formula:

An alkylarylene moiety may be substituted (e.g. with a substituentgroup) on the alkylene moiety or the arylene linker (e.g. at carbons 2,3, 4, or 6) with halogen, oxo, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂CH₃—SO₃H, —OSO₃H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted C₁-C₅ alkyl orsubstituted or unsubstituted 2 to 5 membered heteroalkyl). Inembodiments, the alkylarylene is unsubstituted.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and“heteroaryl”) includes both substituted and unsubstituted forms of theindicated radical. Preferred substituents for each type of radical areprovided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″,—ONR′R″, —NR′C(O)NR″NR′″R″″, —CN, —NO₂, —NR′SO₂R″, —NR′C(O)R″,—NR′C(O)—OR″, —NR′OR″, in a number ranging from zero to (2m′+1), wherem′ is the total number of carbon atoms in such radical. R, R′, R″, R′″,and R″″ each preferably independently refer to hydrogen, halogen,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl (e.g., aryl substituted with 1-3 halogens),substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When acompound described herein includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″,and R″″ group when more than one of these groups is present. When R′ andR″ are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example,—NR′R″ includes, but is not limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂CH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″, —ONR′R″,—NR′C(O)NR″NR′″R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, —NR′SO₂R″, —NR′C(O)R″, —NR′C(O)—OR″, —NR′OR″, ina number ranging from zero to the total number of open valences on thearomatic ring system; and where R′, R″, R′″, and R″″ are preferablyindependently selected from hydrogen, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl. When a compound described herein includes morethan one R group, for example, each of the R groups is independentlyselected as are each R′, R″, R′″, and R″″ groups when more than one ofthese groups is present.

Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl,heteroaryl, cycloalkylene, heterocycloalkylene, arylene, orheteroarylene) may be depicted as substituents on the ring rather thanon a specific atom of a ring (commonly referred to as a floatingsubstituent). In such a case, the substituent may be attached to any ofthe ring atoms (obeying the rules of chemical valency) and in the caseof fused rings or spirocyclic rings, a substituent depicted asassociated with one member of the fused rings or spirocyclic rings (afloating substituent on a single ring), may be a substituent on any ofthe fused rings or spirocyclic rings (a floating substituent on multiplerings). When a substituent is attached to a ring, but not a specificatom (a floating substituent), and a subscript for the substituent is aninteger greater than one, the multiple substituents may be on the sameatom, same ring, different atoms, different fused rings, differentspirocyclic rings, and each substituent may optionally be different.Where a point of attachment of a ring to the remainder of a molecule isnot limited to a single atom (a floating substituent), the attachmentpoint may be any atom of the ring and in the case of a fused ring orspirocyclic ring, any atom of any of the fused rings or spirocyclicrings while obeying the rules of chemical valency. Where a ring, fusedrings, or spirocyclic rings contain one or more ring heteroatoms and thering, fused rings, or spirocyclic rings are shown with one more floatingsubstituents (including, but not limited to, points of attachment to theremainder of the molecule), the floating substituents may be bonded tothe heteroatoms. Where the ring heteroatoms are shown bound to one ormore hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and athird bond to a hydrogen) in the structure or formula with the floatingsubstituent, when the heteroatom is bonded to the floating substituent,the substituent will be understood to replace the hydrogen, whileobeying the rules of chemical valency.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′— (C″R″R′″)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″, and R′″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), Boron (B),and silicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   -   (A) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂,        —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,        —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,        —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,        —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,        —OCH₂Cl, —OCH₂Br, —OCH₂F, —OCH₂I, unsubstituted alkyl (e.g.,        C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted        heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8        membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or        4 to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,        C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3        to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6        membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted        aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted        heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9        membered, or 5 to 6 membered), and    -   (B) alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),        heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8        membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or        4 to 5 membered), cycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆,        or C₅-C₆), heterocycloalkyl (e.g., 3 to 10 membered, 3 to 8        membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or        5 to 6 membered), aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or        heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9        membered, or 5 to 6 membered), substituted with at least one        substituent selected from:        -   (i) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂,            —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,            —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂N H₂, —NHNH₂,            —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,            —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,            —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂F, —OCH₂I,            unsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆,            C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 20            membered, 2 to 12 membered, 2 to 8 membered, 2 to 6            membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5            membered), unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,            C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl            (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4            to 6 membered, 4 to 5 membered, or 5 to 6 membered),            unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or            unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10            membered, 5 to 9 membered, or 5 to 6 membered), and        -   (ii) alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or            C₁-C₂), heteroalkyl (e.g., 2 to 20 membered, 2 to 12            membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered,            2 to 3 membered, or 4 to 5 membered), cycloalkyl (e.g.,            C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), heterocycloalkyl            (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4            to 6 membered, 4 to 5 membered, or 5 to 6 membered), aryl            (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or heteroaryl (e.g., 5 to            12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6            membered), substituted with at least one substituent            selected from:            -   (a) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,                —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂B r, —CH₂F, —CH₂I,                —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,                —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,                —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃,                —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,                —OCH₂Cl, —OCH₂Br, —OCH₂F, —OCH₂I, unsubstituted alkyl                (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),                unsubstituted heteroalkyl (e.g., 2 to 20 membered, 2 to                12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6                membered, 2 to 3 membered, or 4 to 5 membered),                unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆,                C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g.,                3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to                6 membered, 4 to 5 membered, or 5 to 6 membered),                unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or                unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to                10 membered, 5 to 9 membered, or 5 to 6 membered), and            -   (b) alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or                C₁-C₂), heteroalkyl (e.g., 2 to 20 membered, 2 to 12                membered, 2 to 8 membered, 2 to 6 membered, 4 to 6                membered, 2 to 3 membered, or 4 to 5 membered),                cycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or                C₅-C₆), heterocycloalkyl (e.g., 3 to 10 membered, 3 to 8                membered, 3 to 6 membered, 4 to 6 membered, 4 to 5                membered, or 5 to 6 membered), aryl (e.g., C₆-C₁₂,                C₆-C₁₀, or phenyl), or heteroaryl (e.g., 5 to 12                membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6                membered), substituted with at least one substituent                selected from: oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃,                —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂B r, —CH₂F,                —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,                —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,                —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃,                —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,                —OCH₂Cl, —OCH₂Br, —OCH₂F, —OCH₂I, unsubstituted alkyl                (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),                unsubstituted heteroalkyl (e.g., 2 to 20 membered, 2 to                12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6                membered, 2 to 3 membered, or 4 to 5 membered),                unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆,                C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g.,                3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to                6 membered, 4 to 5 membered, or 5 to 6 membered),                unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or                unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to                10 membered, 5 to 9 membered, or 5 to 6 membered).

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. In other embodiments, at least one or all of thesegroups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 8 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 10 membered heteroarylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 7 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 9 membered heteroarylene. In someembodiments, the compound is a chemical species set forth in theExamples section, figures, or tables below.

In embodiments, a substituted or unsubstituted moiety (e.g., substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, and/orsubstituted or unsubstituted heteroarylene) is unsubstituted (e.g., isan unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,unsubstituted heteroaryl, unsubstituted alkylene, unsubstitutedheteroalkylene, unsubstituted cycloalkylene, unsubstitutedheterocycloalkylene, unsubstituted arylene, and/or unsubstitutedheteroarylene, respectively). In embodiments, a substituted orunsubstituted moiety (e.g., substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, and/or substituted or unsubstituted heteroarylene) issubstituted (e.g., is a substituted alkyl, substituted heteroalkyl,substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl,substituted heteroaryl, substituted alkylene, substitutedheteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene, respectively).

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one substituent group,wherein if the substituted moiety is substituted with a plurality ofsubstituent groups, each substituent group may optionally be different.In embodiments, if the substituted moiety is substituted with aplurality of substituent groups, each substituent group is different.

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one size-limited substituentgroup, wherein if the substituted moiety is substituted with a pluralityof size-limited substituent groups, each size-limited substituent groupmay optionally be different. In embodiments, if the substituted moietyis substituted with a plurality of size-limited substituent groups, eachsize-limited substituent group is different.

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one lower substituent group,wherein if the substituted moiety is substituted with a plurality oflower substituent groups, each lower substituent group may optionally bedifferent. In embodiments, if the substituted moiety is substituted witha plurality of lower substituent groups, each lower substituent group isdifferent.

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one substituent group,size-limited substituent group, or lower substituent group; wherein ifthe substituted moiety is substituted with a plurality of groupsselected from substituent groups, size-limited substituent groups, andlower substituent groups; each substituent group, size-limitedsubstituent group, and/or lower substituent group may optionally bedifferent. In embodiments, if the substituted moiety is substituted witha plurality of groups selected from substituent groups, size-limitedsubstituent groups, and lower substituent groups; each substituentgroup, size-limited substituent group, and/or lower substituent group isdifferent.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisometricforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers areencompassed within the scope of the present invention. The compounds ofthe present invention do not include those that are known in art to betoo unstable to synthesize and/or isolate. The present invention ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

It should be noted that throughout the application that alternatives arewritten in Markush groups, for example, each amino acid position thatcontains more than one possible amino acid. It is specificallycontemplated that each member of the Markush group should be consideredseparately, thereby comprising another embodiment, and the Markush groupis not to be read as a single unit.

“Analog,” or “analogue” is used in accordance with its plain ordinarymeaning within Chemistry and Biology and refers to a chemical compoundthat is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in thereplacement of one atom by an atom of a different element, or in thepresence of a particular functional group, or the replacement of onefunctional group by another functional group, or the absolutestereochemistry of one or more chiral centers of the reference compound.Accordingly, an analog is a compound that is similar or comparable infunction and appearance but not in structure or origin to a referencecompound.

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls.

Moreover, where a moiety is substituted with an R substituent, the groupmay be referred to as “R-substituted.” Where a moiety is R-substituted,the moiety is substituted with at least one R substituent and each Rsubstituent is optionally different. Where a particular R group ispresent in the description of a chemical genus (such as Formula (I)), aRoman alphabetic symbol or additional number may be used to distinguisheach appearance of that particular R group. For example, where multipleR¹ substituents are present, each R¹ substituent may be distinguished asR^(1.1) R^(1.2), R^(1.3), R^(1.4), etc., wherein each of R^(1.1)R^(1.2), R^(1.3), R^(1.4), etc. is defined within the scope of thedefinition of R¹ and optionally differently.

A “detectable moiety” as used herein refers to a moiety that can becovalently or noncovalently attached to a compound or biomolecule thatcan be detected for instance, using techniques known in the art. Inembodiments, the detectable moiety is covalently attached. Thedetectable moiety may provide for imaging of the attached compound orbiomolecule. The detectable moiety may indicate the contacting betweentwo compounds. Exemplary detectable moieties are fluorophores,antibodies, reactive dyes, radio-labeled moieties, magnetic contrastagents, and quantum dots. Exemplary fluorophores include fluorescein,rhodamine, GFP, coumarin, FITC, Alexa fluor, Cy3, Cy5, BODIPY, andcyanine dyes. Exemplary radionuclides include Fluorine-18, Gallium-68,and Copper-64. Exemplary magnetic contrast agents include gadolinium,iron oxide and iron platinum, and manganese.

Description of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and thelike. Also included are salts of amino acids such as arginate and thelike, and salts of organic acids like glucuronic or galactunoric acidsand the like (see, for example, Berge et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

Thus, the compounds of the present invention may exist as salts, such aswith pharmaceutically acceptable acids. The present invention includessuch salts. Non-limiting examples of such salts include hydrochlorides,hydrobromides, phosphates, sulfates, methanesulfonates, nitrates,maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g.,(+)-tartrates, (−)-tartrates, or mixtures thereof including racemicmixtures), succinates, benzoates, and salts with amino acids such asglutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyliodide, and the like). These salts may be prepared by methods known tothose skilled in the art.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compound maydiffer from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Prodrugs of the compounds described herein may be convertedin vivo after administration. Additionally, prodrugs can be converted tothe compounds of the present invention by chemical or biochemicalmethods in an ex vivo environment, such as, for example, when contactedwith a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

The terms “polypeptide,” “peptide” and “protein” are usedinterchangeably herein to refer to a polymer of amino acid residues,wherein the polymer may optionally be conjugated to a moiety that doesnot consist of amino acids. The terms apply to amino acid polymers inwhich one or more amino acid residue is an artificial chemical mimeticof a corresponding naturally occurring amino acid, as well as tonaturally occurring amino acid polymers and non-naturally occurringamino acid polymer.

A polypeptide, or a cell is “recombinant” when it is artificial orengineered, or derived from or contains an artificial or engineeredprotein or nucleic acid (e.g. non-natural or not wild type). Forexample, a polynucleotide that is inserted into a vector or any otherheterologous location, e.g., in a genome of a recombinant organism, suchthat it is not associated with nucleotide sequences that normally flankthe polynucleotide as it is found in nature is a recombinantpolynucleotide. A protein expressed in vitro or in vivo from arecombinant polynucleotide is an example of a recombinant polypeptide.Likewise, a polynucleotide sequence that does not appear in nature, forexample a variant of a naturally occurring gene, is recombinant.

“Co-administer” it is meant that a composition described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies. The compounds of theinvention can be administered alone or can be coadministered to thepatient. Coadministration is meant to include simultaneous or sequentialadministration of the compounds individually or in combination (morethan one compound). Thus, the preparations can also be combined, whendesired, with other active substances (e.g. to reduce metabolicdegradation). The compositions of the present invention can be deliveredtransdermally, by a topical route, or formulated as applicator sticks,solutions, suspensions, emulsions, gels, creams, ointments, pastes,jellies, paints, powders, and aerosols.

A “cell” as used herein, refers to a cell carrying out metabolic orother function sufficient to preserve or replicate its genomic DNA. Acell can be identified by well-known methods in the art including, forexample, presence of an intact membrane, staining by a particular dye,ability to produce progeny or, in the case of a gamete, ability tocombine with a second gamete to produce a viable offspring. Cells mayinclude prokaryotic and eukaroytic cells. Prokaryotic cells include butare not limited to bacteria. Eukaryotic cells include but are notlimited to yeast cells and cells derived from plants and animals, forexample mammalian, insect (e.g., spodoptera) and human cells. Cells maybe useful when they are naturally nonadherent or have been treated notto adhere to surfaces, for example by trypsinization.

The terms “treating” or “treatment” refers to any indicia of success inthe treatment or amelioration of an injury, disease, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; improving a patient's physical or mental well-being.The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. For example,the certain methods presented herein successfully treat cancer bydecreasing the incidence of cancer and or causing remission of cancer.In some embodiments of the compositions or methods described herein,treating cancer includes slowing the rate of growth or spread of cancercells, reducing metastasis, or reducing the growth of metastatic tumors.The term “treating” and conjugations thereof, include prevention of aninjury, pathology, condition, or disease. In embodiments, “treating”does not include prevention.

An “effective amount” is an amount sufficient for a compound toaccomplish a stated purpose relative to the absence of the compound(e.g. achieve the effect for which it is administered, treat a disease,reduce enzyme activity, increase enzyme activity, reduce signalingpathway, reduce one or more symptoms of a disease or condition (e.g.reduce signaling pathway stimulated by GTP bound K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B), reduce the signaling pathway activityof K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B), reduce thesignaling pathway activity of K-Ras4A, reduce the signaling pathwayactivity of K-Ras4B, reduce the signaling pathway activity of a mutantK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B), inhibit the bindingof K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) to SOS, inhibitthe binding of K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) to aGEF, reduce the localization of K-Ras (e.g., human K-Ras 4A and/or humanK-Ras 4B) to a membrane, reduce the prenylation of K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B), inhibit the localization of K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) to a membrane). An exampleof an “effective amount” is an amount sufficient to contribute to thetreatment, prevention, or reduction of a symptom or symptoms of adisease, which could also be referred to as a “therapeutically effectiveamount.” A “reduction” of a symptom or symptoms (and grammaticalequivalents of this phrase) means decreasing of the severity orfrequency of the symptom(s), or elimination of the symptom(s). A“prophylactically effective amount” of a drug is an amount of a drugthat, when administered to a subject, will have the intendedprophylactic effect, e.g., preventing or delaying the onset (orreoccurrence) of an injury, disease, pathology or condition, or reducingthe likelihood of the onset (or reoccurrence) of an injury, disease,pathology, or condition, or their symptoms. The full prophylactic effectdoes not necessarily occur by administration of one dose, and may occuronly after administration of a series of doses. Thus, a prophylacticallyeffective amount may be administered in one or more administrations. An“activity decreasing amount,” as used herein, refers to an amount ofantagonist required to decrease the activity of an enzyme relative tothe absence of the antagonist. A “function disrupting amount,” as usedherein, refers to the amount of antagonist required to disrupt thefunction of an enzyme or protein relative to the absence of theantagonist (e.g. disrupt the protein-protein interaction between K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) and a signaling pathwaybinding protein such as PI3K, disrupt the interaction of K-Ras (e.g.,human K-Ras 4A and/or human K-Ras 4B) and GEF, disrupt the interactionof K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) and SOS, disruptthe interaction of K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)with Raf, disrupt the localization of K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B) to a membrane, disrupt the prenylation of K-Ras (e.g.,human K-Ras 4A and/or human K-Ras 4B)). The exact amounts will depend onthe purpose of the treatment, and will be ascertainable by one skilledin the art using known techniques (see, e.g., Lieberman, PharmaceuticalDosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technologyof Pharmaceutical Compounding (1999); Pickar, Dosage Calculations(1999); and Remington: The Science and Practice of Pharmacy, 20thEdition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

“Control” or “control experiment” is used in accordance with its plainordinary meaning and refers to an experiment in which the subjects orreagents of the experiment are treated as in a parallel experimentexcept for omission of a procedure, reagent, or variable of theexperiment. In some instances, the control is used as a standard ofcomparison in evaluating experimental effects. In some embodiments, acontrol is the measurement of the activity (e.g. signaling pathway) of aprotein (e.g. K-Ras, mutant K-Ras, K-Ras G12C, K-Ras G12D, K-Ras G13C,K-Ras G13D, K-Ras G12V, K-Ras G12S) in the absence of a compound asdescribed herein (including embodiments, examples, figures, or Tables).

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules, or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated; however, the resulting reaction product can be produceddirectly from a reaction between the added reagents or from anintermediate from one or more of the added reagents which can beproduced in the reaction mixture.

The term “contacting” may include allowing two species to react,interact, or physically touch, wherein the two species may be a compoundas described herein and a protein or enzyme (e.g. K-Ras, K-Ras4A,K-Ras4B, mutant K-Ras, K-Ras G12C, K-Ras G13C, K-Ras G12D, K-Ras G13D,K-Ras G12V, K-Ras G12S). In some embodiments, the protein may be K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B). In some embodiments, theprotein may be a mutant K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B) (e.g. K-Ras G12C, K-Ras G13C, K-Ras G12D, K-Ras G13D, K-Ras G12V,K-Ras G12S). In some embodiments, the protein may be K-Ras4A. In someembodiments, the protein may be K-Ras4B. In some embodiments contactingincludes allowing a compound described herein to interact with a proteinor enzyme that is involved in a signaling pathway.

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” andthe like in reference to a protein-inhibitor interaction meansnegatively affecting (e.g. decreasing) the activity or function of theprotein (e.g. decreasing the signaling pathway stimulated by GTP boundK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) (e.g. K-Ras, K-RasG12C, K-Ras G13C, K-Ras G12D, K-Ras G13D, K-Ras G12V, K-Ras G12S),nucleotide exchange, effector protein binding, effector proteinactivation, guanine exchange factor (GEF) binding, SOS binding,GEF-facilitated nucleotide exchange, phosphate release, nucleotiderelease, nucleotide binding, membrane localization, prenylation of theprotein) relative to the activity or function of the protein in theabsence of the inhibitor. In some embodiments inhibition refers toreduction of a disease or symptoms of disease. In some embodiments,inhibition refers to a reduction in the activity of a signaltransduction pathway or signaling pathway (e.g. reduction of a pathwayinvolving GTP bound K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)(e.g. K-Ras, K-Ras G12C, K-Ras G13C, K-Ras G12D, K-Ras G13D, K-Ras G12V,K-Ras G12S), reduction of a pathway involving mutant K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) (e.g. K-Ras G12C, K-Ras G13C, K-RasG12D, K-Ras G13D, K-Ras G12V, K-Ras G12S)). Thus, inhibition includes,at least in part, partially or totally blocking stimulation, decreasing,preventing, or delaying activation, or inactivating, desensitizing, ordown-regulating the signaling pathway or enzymatic activity or theamount of a protein (e.g. K-Ras, K-Ras G12C, K-Ras G13C, K-Ras G12D,K-Ras G13D, K-Ras G12V, K-Ras G12S). In some embodiments, inhibitionrefers to inhibition of interactions of K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) (K-Ras, K-Ras G12C, K-Ras G13C, K-Ras G12D, K-RasG13D, K-Ras G12V, K-Ras G12S) with signaling pathway binding partners(e.g. PI3K, SOS, Raf). In some embodiments, inhibition refers toinhibition of interactions of K-Ras (e.g., human K-Ras 4A and/or humanK-Ras 4B) with a GEF (e.g. SOS). In some embodiments, inhibition refersto inhibition of K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)prenylation. In some embodiments, inhibition refers to inhibition ofK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) localization. In someembodiments, inhibition refers to inhibition of K-Ras (e.g., human K-Ras4A and/or human K-Ras 4B) membrane localization.

The term “modulator” refers to a composition that increases or decreasesthe level of a target molecule or the function (e.g., effector proteinbinding, effector protein activation, guanine exchange factor (GEF)binding, SOS binding, prenylation, localization) of a target molecule orthe physical state (e.g. K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B) subcellular localization, K-Ras (e.g., human K-Ras 4A and/or humanK-Ras 4B) post-translational processing, K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) post-translational modifications (prenylation))of the target of the molecule (e.g. a target may be K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) and the function may be to hydrolyze GTPor activate a signaling pathway that is activated by GTP bound K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B), interaction of K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) with protein bindingpartners (e.g. PI3K, SOS, Raf)) relative to the absence of thecomposition. In some embodiments, a K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B) disease modulator is a compound that reduces theseverity of one or more symptoms of a disease associated with K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) (e.g. cancer, metastaticcancer) relative to the absence of the compound. A K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) modulator is a compound that increasesor decreases the activity or function or level of activity or level offunction of K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) or levelof K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) or level of K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) in a particular physicalstate relative to the absence of the compound. A mutant K-Ras (e.g.,human K-Ras 4A and/or human K-Ras 4B) modulator is a compound that thatincreases or decreases the activity or function or level of activity orlevel of function of mutant K-Ras (e.g., human K-Ras 4A and/or humanK-Ras 4B) or level of mutant K-Ras (e.g., human K-Ras 4A and/or humanK-Ras 4B) or level of mutant K-Ras (e.g., human K-Ras 4A and/or humanK-Ras 4B) in a particular physical state relative to the absence of themodulator (e.g., a compound described herein). A K-Ras G12C modulator,K-Ras G12D modulator, K-Ras G13C modulator, K-Ras G12V modulator, K-RasG12S modulator, or K-Ras G13D modulator is a compound that increases ordecreases the activity or function or level of activity or level offunction of that particular mutant K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B) or level of that particular mutant K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) or level of that particular mutant K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) in a particular physicalstate relative to the absence of the compound. A K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) inhibitor is a compound that decreasesthe activity or function or level of activity or level of function ofK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) or level of K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) or level of K-Ras (e.g.,human K-Ras 4A and/or human K-Ras 4B) in a particular physical staterelative to the absence of the compound. A mutant K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) inhibitor is a compound that thatdecreases the activity or function or level of activity or level offunction of mutant K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) orlevel of mutant K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) orlevel of mutant K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) in aparticular physical state relative to the absence of the compound. AK-Ras G12C inhibitor, K-Ras G12D inhibitor, K-Ras G13C inhibitor, K-RasG12V inhibitor, K-Ras G12S inhibitor, or K-Ras G13D inhibitor is acompound that decreases the activity or function or level of activity orlevel of function of that particular mutant K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) or level of that particular mutant K-Ras (e.g.,human K-Ras 4A and/or human K-Ras 4B) or level of that particular mutantK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) in a particularphysical state relative to the absence of the compound.

The term “modulate” is used in accordance with its plain ordinarymeaning and refers to the act of changing or varying one or moreproperties. “Modulation” refers to the process of changing or varyingone or more properties. For example, as applied to the effects of amodulator on a target protein, to modulate means to change by increasingor decreasing a property or function of the target molecule or theamount of the target molecule.

“Patient” or “subject in need thereof” refers to a living organismsuffering from or prone to a disease or condition that can be treated byadministration of a pharmaceutical composition as provided herein.Non-limiting examples include humans, other mammals, bovines, rats,mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammaliananimals. In some embodiments, a patient is human.

“Disease” or “condition” refer to a state of being or health status of apatient or subject capable of being treated with the compounds ormethods provided herein. In some embodiments, the disease is a diseaserelated to (e.g. caused by) a K-Ras (e.g., human K-Ras 4A and/or humanK-Ras 4B). In some embodiments, the disease is a disease related to(e.g. caused by) a K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)(e.g. K-Ras G12C, G13C, G12D, G12V, G12S, or G13D) or aberrant K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) signaling pathway activity(e.g. lung cancer, breast cancer, colon cancer, colorectal cancer,pancreatic cancer, leukemia). Examples of diseases, disorders, orconditions include, but are not limited to cancer. Examples of diseases,disorders, or conditions include, but are not limited to MYH-associatedpolyposis. In some instances, “disease” or “condition” refers to cancer.In some instances, “disease” or “condition” refers to MYH-associatedpolyposis. In some further instances, “cancer” refers to human cancersand carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc.,including solid and lymphoid cancers, kidney, breast, lung, bladder,colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin,uterine, testicular, glioma, esophagus, and liver cancer, includinghepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma,non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Celllymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML),or multiple myeloma.

As used herein, the term “cancer” refers to all types of cancer,neoplasm or malignant tumors found in mammals (e.g. humans), includingleukemia, lymphoma, carcinomas and sarcomas. Exemplary cancers that maybe treated with a compound or method provided herein include cancer ofthe thyroid, endocrine system, brain, breast, cervix, colon, head &neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma,ovary, sarcoma, stomach, uterus, Medulloblastoma, colorectal cancer,pancreatic cancer. Additional examples include, Hodgkin's Disease,Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma,glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primarythrombocytosis, primary macroglobulinemia, primary brain tumors, cancer,malignant pancreatic insulanoma, malignant carcinoid, urinary bladdercancer, premalignant skin lesions, testicular cancer, lymphomas, thyroidcancer, neuroblastoma, esophageal cancer, genitourinary tract cancer,malignant hypercalcemia, endometrial cancer, adrenal cortical cancer,neoplasms of the endocrine or exocrine pancreas, medullary thyroidcancer, medullary thyroid carcinoma, melanoma, colorectal cancer,papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

The term “leukemia” refers broadly to progressive, malignant diseases ofthe blood-forming organs and is generally characterized by a distortedproliferation and development of leukocytes and their precursors in theblood and bone marrow. Leukemia is generally clinically classified onthe basis of (1) the duration and character of the disease-acute orchronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid(lymphogenous), or monocytic; and (3) the increase or non-increase inthe number abnormal cells in the blood-leukemic or aleukemic(subleukemic). Exemplary leukemias that may be treated with a compoundor method provided herein include, for example, acute nonlymphocyticleukemia, chronic lymphocytic leukemia, acute granulocytic leukemia,chronic granulocytic leukemia, acute promyelocytic leukemia, adultT-cell leukemia, aleukemic leukemia, a leukocythemic leukemia,basophylic leukemia, blast cell leukemia, bovine leukemia, chronicmyelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilicleukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia,hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia,acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia,lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia,megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia,myeloblastic leukemia, myelocytic leukemia, myeloid granulocyticleukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cellleukemia, multiple myeloma, plasmacytic leukemia, promyelocyticleukemia, Rieder cell leukemia, Schilling's leukemia, stem cellleukemia, subleukemic leukemia, or undifferentiated cell leukemia.

As used herein, the term “lymphoma” refers to a group of cancersaffecting hematopoietic and lymphoid tissues. It begins in lymphocytes,the blood cells that are found primarily in lymph nodes, spleen, thymus,and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma andHodgkin's disease. Hodgkin's disease represents approximately 15% of alldiagnosed lymphomas. This is a cancer associated with Reed-Sternbergmalignant B lymphocytes. Non-Hodgkin's lymphomas (NHL) can be classifiedbased on the rate at which cancer grows and the type of cells involved.There are aggressive (high grade) and indolent (low grade) types of NHL.Based on the type of cells involved, there are B-cell and T-cell NHLs.Exemplary B-cell lymphomas that may be treated with a compound or methodprovided herein include, but are not limited to, small lymphocyticlymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zonelymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell)lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt'slymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, orprecursor B-lymphoblastic lymphoma. Exemplary T-cell lymphomas that maybe treated with a compound or method provided herein include, but arenot limited to, cunateous T-cell lymphoma, peripheral T-cell lymphoma,anaplastic large cell lymphoma, mycosis fungoides, and precursorT-lymphoblastic lymphoma.

The term “sarcoma” generally refers to a tumor which is made up of asubstance like the embryonic connective tissue and is generally composedof closely packed cells embedded in a fibrillar or homogeneoussubstance. Sarcomas that may be treated with a compound or methodprovided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma,melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adiposesarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma,botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma,Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing'ssarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma,granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmentedhemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma,immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma,Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymomasarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma,serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

The term “melanoma” is taken to mean a tumor arising from themelanocytic system of the skin and other organs. Melanomas that may betreated with a compound or method provided herein include, for example,acral-lentiginous melanoma, amelanotic melanoma, benign juvenilemelanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma,juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodularmelanoma, subungal melanoma, or superficial spreading melanoma.

The term “carcinoma” refers to a malignant new growth made up ofepithelial cells tending to infiltrate the surrounding tissues and giverise to metastases. Exemplary carcinomas that may be treated with acompound or method provided herein include, for example, medullarythyroid carcinoma, familial medullary thyroid carcinoma, acinarcarcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cysticcarcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolarcarcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinomabasocellulare, basaloid carcinoma, basosquamous cell carcinoma,bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogeniccarcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorioniccarcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma,cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum,cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma,carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoidcarcinoma, carcinoma epitheliale adenoides, exophytic carcinoma,carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma,gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare,glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma,hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma,hyaline carcinoma, hypernephroid carcinoma, infantile embryonalcarcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelialcarcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cellcarcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatouscarcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullarycarcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma,carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma,carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes,nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans,osteoid carcinoma, papillary carcinoma, periportal carcinoma,preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma,renal cell carcinoma of kidney, reserve cell carcinoma, carcinomasarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinomascroti, signet-ring cell carcinoma, carcinoma simplex, small-cellcarcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cellcarcinoma, carcinoma spongiosum, squamous carcinoma, squamous cellcarcinoma, string carcinoma, carcinoma telangiectaticum, carcinomatelangiectodes, transitional cell carcinoma, carcinoma tuberosum,tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

“Ras associated cancer” (also referred to herein as “Ras relatedcancer”) refers to a cancer caused by aberrant Ras activity, level, orsignaling. A “cancer associated with aberrant K-Ras activity” (alsoreferred to herein as “K-Ras related cancer”) is a cancer caused byaberrant K-Ras activity or signaling (e.g. a mutant K-Ras). K-Rasrelated cancers may include lung cancer, non-small cell lung cancer,breast cancer, leukemia, pancreatic cancer, colon cancer, colorectalcancer. Other cancers that are associated with aberrant activity of oneor more of K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) and mutantK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) (including K-RasG12C, K-Ras G13C, K-Ras G12D, K-Ras G12V, K-Ras G12S, K-Ras G13Dmutants) are well known in the art and determining such cancers arewithin the skill of a person of skill in the art.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. One of skill inthe art will recognize that other pharmaceutical excipients are usefulin the present invention.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,intraperitoneal, intramuscular, intralesional, intrathecal, intranasalor subcutaneous administration, or the implantation of a slow-releasedevice, e.g., a mini-osmotic pump, to a subject. Administration is byany route, including parenteral and transmucosal (e.g., buccal,sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal).Parenteral administration includes, e.g., intravenous, intramuscular,intra-arteriole, intradermal, subcutaneous, intraperitoneal,intraventricular, and intracranial. Other modes of delivery include, butare not limited to, the use of liposomal formulations, intravenousinfusion, transdermal patches, etc. By “co-administer” it is meant thata composition described herein is administered at the same time, justprior to, or just after the administration of one or more additionaltherapies, for example cancer therapies such as chemotherapy, hormonaltherapy, radiotherapy, or immunotherapy. The compounds of the inventioncan be administered alone or can be coadministered to the patient.Coadministration is meant to include simultaneous or sequentialadministration of the compounds individually or in combination (morethan one compound). Thus, the preparations can also be combined, whendesired, with other active substances (e.g. to reduce metabolicdegradation). The compositions of the present invention can be deliveredby transdermally, by a topical route, formulated as applicator sticks,solutions, suspensions, emulsions, gels, creams, ointments, pastes,jellies, paints, powders, and aerosols.

The term “administer (or administering) a Ras inhibitor” or “administer(or administering) a K-Ras inhibitor” means administering a compoundthat inhibits the activity or level (e.g. amount) or level of asignaling pathway of one or more K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B) proteins (K-Ras, mutant K-Ras, K-Ras G12C, K-Ras G12V,K-Ras G12S, K-Ras G12D, K-Ras G13C, K-Ras G13D). Administration mayinclude, without being limited by mechanism, allowing sufficient timefor the K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) inhibitor toreduce the activity of one or more K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B) proteins or for the K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B) inhibitor to reduce one or more symptoms of a disease(e.g. cancer, wherein the K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B) inhibitor may arrest the cell cycle, slow the cell cycle, reduce DNAreplication, reduce cell replication, reduce cell growth, reducemetastasis, or cause cell death).

The compounds described herein can be used in combination with oneanother, with other active agents known to be useful in treating adisease associated with cells expressing a particular K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) or mutant K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) (e.g. cancer), or with adjunctive agents that maynot be effective alone, but may contribute to the efficacy of the activeagent. In embodiments, the administering does not include administrationof any active agent other than the recited active agent.

In some embodiments, co-administration includes administering one activeagent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a secondactive agent. Co-administration includes administering two active agentssimultaneously, approximately simultaneously (e.g., within about 1, 5,10, 15, 20, or 30 minutes of each other), or sequentially in any order.In some embodiments, co-administration can be accomplished byco-formulation, i.e., preparing a single pharmaceutical compositionincluding both active agents. In other embodiments, the active agentscan be formulated separately. In another embodiment, the active and/oradjunctive agents may be linked or conjugated to one another.

As a non-limiting example, the compounds described herein can beco-administered with conventional chemotherapeutic agents includingalkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil,busulfan, melphalan, mechlorethamine, uramustine, thiotepa,nitrosoureas, etc.), anti-metabolites (e.g., 5-fluorouracil,azathioprine, methotrexate, leucovorin, capecitabine, cytarabine,floxuridine, fludarabine, gemcitabine, pemetrexed, raltitrexed, etc.),plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine,podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors(e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposidephosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin,adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin,mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g.cisplatin, oxaloplatin, carboplatin, etc.), and the like.

The compounds described herein can also be co-administered withconventional hormonal therapeutic agents including, but not limited to,steroids (e.g., dexamethasone), finasteride, aromatase inhibitors,tamoxifen, and gonadotropin-releasing hormone agonists (GnRH) such asgoserelin.

Additionally, the compounds described herein can be co-administered withconventional immunotherapeutic agents including, but not limited to,immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole,interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g.,anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonalantibodies), immunotoxins (e.g., anti-CD33 monoclonalantibody-calicheamicin conjugate, anti-CD22 monoclonalantibody-pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy(e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I,etc.).

In a further embodiment, the compounds described herein can beco-administered with conventional radiotherapeutic agents including, butnot limited to, radionuclides such as ⁴⁷Sc, ⁶⁴Cu, ⁶⁷Cu, ⁸⁹Sr, ⁸⁶Y, ⁸⁷Y,⁹⁰Y, ¹⁰⁵Rh, ¹¹¹Ag, ¹¹¹In, ^(117m)Sn, ¹⁴⁹Pm, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁸⁶Re,¹⁸⁸Re, ²¹¹At, and ²¹²Bi, optionally conjugated to antibodies directedagainst tumor antigens.

In therapeutic use for the treatment of cancer, compound utilized in thepharmaceutical compositions of the present invention may be administeredat the initial dosage of about 0.001 mg/kg to about 1000 mg/kg daily. Adaily dose range of about 0.01 mg/kg to about 500 mg/kg, or about 0.1mg/kg to about 200 mg/kg, or about 1 mg/kg to about 100 mg/kg, or about10 mg/kg to about 50 mg/kg, can be used. The dosages, however, may bevaried depending upon the requirements of the patient, the severity ofthe condition being treated, and the compound or drug being employed.For example, dosages can be empirically determined considering the typeand stage of cancer diagnosed in a particular patient. The doseadministered to a patient, in the context of the present invention,should be sufficient to affect a beneficial therapeutic response in thepatient over time. The size of the dose will also be determined by theexistence, nature, and extent of any adverse side-effects that accompanythe administration of a compound in a particular patient. Determinationof the proper dosage for a particular situation is within the skill ofthe practitioner. Generally, treatment is initiated with smaller dosageswhich are less than the optimum dose of the compound. Thereafter, thedosage is increased by small increments until the optimum effect undercircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

The compounds described herein can be used in combination with oneanother, with other active agents known to be useful in treating canceror with adjunctive agents that may not be effective alone, but maycontribute to the efficacy of the active agent.

The term “associated” or “associated with” in the context of a substanceor substance activity or function associated with a disease (e.g. aprotein associated disease, a cancer associated with aberrant K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) activity, K-Ras (e.g.,human K-Ras 4A and/or human K-Ras 4B) associated cancer, mutant K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) associated cancer,activated K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) associatedcancer, K-Ras G12C associated cancer, K-Ras G12V associated cancer,K-Ras G12S associated cancer, K-Ras G13C associated cancer, K-Ras G12Dassociated cancer, K-Ras G13D associated cancer) means that the disease(e.g. cancer) is caused by (in whole or in part), or a symptom of thedisease is caused by (in whole or in part) the substance or substanceactivity or function. For example, a cancer associated with aberrantK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) activity or functionmay be a cancer that results (entirely or partially) from aberrant K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) activity or function (e.g.enzyme activity, protein-protein interaction, signaling pathway) or acancer wherein a particular symptom of the disease is caused (entirelyor partially) by aberrant K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B) activity or function. As used herein, what is described as beingassociated with a disease, if a causative agent, could be a target fortreatment of the disease. For example, a cancer associated with aberrantK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) activity or functionor a K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) associatedcancer, may be treated with a K-Ras (e.g., human K-Ras 4A and/or humanK-Ras 4B) modulator or K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B) inhibitor, in the instance where increased K-Ras (e.g., human K-Ras4A and/or human K-Ras 4B) activity or function (e.g. signaling pathwayactivity) causes the cancer. For example, a cancer associated with K-RasG12V may be a cancer that a subject with K-Ras G12V is at higher risk ofdeveloping as compared to a subject without K-Ras G12V.

The term “aberrant” as used herein refers to different from normal. Whenused to describe enzymatic activity, aberrant refers to activity that isgreater or less than a normal control or the average of normalnon-diseased control samples. Aberrant activity may refer to an amountof activity that results in a disease, wherein returning the aberrantactivity to a normal or non-disease-associated amount (e.g. byadministering a compound or using a method as described herein), resultsin reduction of the disease or one or more disease symptoms.

“Anti-cancer agent” is used in accordance with its plain ordinarymeaning and refers to a composition (e.g. compound, drug, antagonist,inhibitor, modulator) having antineoplastic properties or the ability toinhibit the growth or proliferation of cells. In some embodiments, ananti-cancer agent is a chemotherapeutic. In some embodiments, ananti-cancer agent is an agent identified herein having utility inmethods of treating cancer. In some embodiments, an anti-cancer agent isan agent approved by the FDA or similar regulatory agency of a countryother than the USA, for treating cancer. Examples of anti-cancer agentsinclude, but are not limited to, MEK (e.g. MEK1, MEK2, or MEK1 and MEK2)inhibitors (e.g. XL518, CI-1040, PD035901, selumetinib/AZD6244,GSK1120212/trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901,U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), alkylatingagents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan,melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,meiphalan), ethylenimine and methylmelamines (e.g., hexamethlymelamine,thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g.,carmustine, lomusitne, semustine, streptozocin), triazenes(decarbazine)), anti-metabolites (e.g., 5-azathioprine, leucovorin,capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folicacid analog (e.g., methotrexate), or pyrimidine analogs (e.g.,fluorouracil, floxouridine, Cytarabine), purine analogs (e.g.,mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g.,vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin,paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g.,irinotecan, topotecan, amsacrine, etoposide (VP 16), etoposidephosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin,adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin,mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g.cisplatin, oxaloplatin, carboplatin), anthracenedione (e.g.,mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazinederivative (e.g., procarbazine), adrenocortical suppressant (e.g.,mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide),antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g.,L-asparaginase), inhibitors of mitogen-activated protein kinasesignaling (e.g. U0126, PD98059, PD184352, PD0325901, ARRY-142886,SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002, Sykinhibitors, mTOR inhibitors, antibodies (e.g., rituxan), gossyphol,genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA),bryostatin, tumor necrosis factor-related apoptosis-inducing ligand(TRAIL), 5-aza-2′-deoxycytidine, all trans retinoic acid, doxorubicin,vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352,20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox L-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol;dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA;ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene;emitefur; epirubicin; epristeride; estramustine analogue; estrogenagonists; estrogen antagonists; etanidazole; etoposide phosphate;exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B 1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen-binding protein; sizofuran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatinstimalamer, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin,acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin;aldesleukin; altretamine; ambomycin; ametantrone acetate;aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase;asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin;bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride;decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene;droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate;eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate;epipropidine; epirubicin hydrochloride; erbulozole; esorubicinhydrochloride; estramustine; estramustine phosphate sodium; etanidazole;etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;fazarabine; fenretinide; floxuridine; fludarabine phosphate;fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; iimofosine; interleukin 1I (includingrecombinant interleukin II, or rlL.sub.2), interferon alfa-2a;interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferonbeta-la; interferon gamma-1b; iproplatin; irinotecan hydrochloride;lanreotide acetate; letrozole; leuprolide acetate; liarozolehydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride;masoprocol; maytansine; mechlorethamine hydrochloride; megestrolacetate; melengestrol acetate; melphalan; menogaril; mercaptopurine;methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide;mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper;mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie;nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin;pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan;piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium;porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol;safingol hydrochloride; semustine; simtrazene; sparfosate sodium;sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin;streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium;tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride, agents that arrest cells in the G2-M phases and/ormodulate the formation or stability of microtubules, (e.g. Taxol™ (i.e.paclitaxel), Taxotere™, compounds comprising the taxane skeleton,Erbulozole (i.e. R-55104), Dolastatin 10 (i.e. DLS-10 and NSC-376128),Mivobulin isethionate (i.e. as CI-980), Vincristine, NSC-639829,Discodermolide (i.e. as NVP-XX-A-296), ABT-751 (Abbott, i.e. E-7010),Altorhyrtins (e.g. Altorhyrtin A and Altorhyrtin C), Spongistatins (e.g.Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4,Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, andSpongistatin 9), Cemadotin hydrochloride (i.e. LU-103793 andNSC-D-669356), Epothilones (e.g. Epothilone A, Epothilone B, EpothiloneC (i.e. desoxyepothilone A or dEpoA), Epothilone D (i.e. KOS-862, dEpoB,and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone BN-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B(i.e. BMS-310705), 21-hydroxyepothilone D (i.e. Desoxyepothilone F anddEpoF), 26-fluoroepothilone, steroids (e.g., dexamethasone),finasteride, aromatase inhibitors, gonadotropin-releasing hormoneagonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids(e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate,megestrol acetate, medroxyprogesterone acetate), estrogens (e.g.,diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen),androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen(e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guérin(BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonalantibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, andanti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonalantibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy(e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I,etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin,epirubicin, topotecan, itraconazole, vindesine, cerivastatin,vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan,clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib,gefitinib, EGFR inhibitors, epidermal growth factor receptor(EGFR)-targeted therapy or therapeutic (e.g. gefitinib (Iressa™),erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™),panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib/BIBW2992,CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST-1306,ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethylerlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002,WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib,sunitinib, dasatinib, Ras inhibitors, or the like.

“Chemotherapeutic” or “chemotherapeutic agent” is used in accordancewith its plain ordinary meaning and refers to a chemical composition orcompound having antineoplastic properties or the ability to inhibit thegrowth or proliferation of cells.

The term “electrophilic” as used herein refers to a chemical group thatis capable of accepting electron density. An “electrophilicsubstituent”, “electrophilic chemical moiety”, or “electrophic moiety”refers to an electron-poor chemical group, substitutent, or moiety(monovalent chemical group), which may react with an electron-donatinggroup, such as a nucleophile, by accepting an electron pair or electrondensity to form a bond. In some embodiments, the electrophilicsubstituent of the compound is capable of reacting with a histidineresidue. In some embodiments, the electrophilic substituent is capableof forming a covalent bond with a histidine residue (e.g., K-Ras (e.g.,human K-Ras 4A and/or human K-Ras 4B) histidine residue, residuecorresponding to H95 of human K-Ras 4A and/or 4B) and may be referred toas a “covalent histidine binding moiety” or “covalent histidine bindingsubstituent”. The covalent bond formed between the electrophilicsubstituent and a nitrogen of the histidine sidechain may be areversible or irreversible bond.

The term “histidine binding moiety” as used herein refers to amonovalent chemical group that is capable of contacting a histidineamino acid (e.g., in a protein, in a K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B) protein) and may interact with the histidine amino acid.In some embodiments, the histidine binding moiety is an electrophilicsubstituent. In embodiments, the histidine binding moiety is capable ofreacting with a histidine residue. In some embodiments, the histidinebinding moiety is capable of forming a covalent bond with a histidineresidue (e.g., K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)histidine residue, residue corresponding to H95 of human K-Ras 4A or 4B)and may be referred to as a “covalent histidine binding moiety” or“covalent histidine binding substituent”. The covalent bond formedbetween the histidine binding moiety and a nitrogen of the histidine maybe a reversible or irreversible bond.

The term “irreversible covalent bond” and “irreversible bond” is used inaccordance with its plain ordinary meaning in the art and refers to theresulting association between atoms or molecules of (e.g., electrophilicchemical moiety and nucleophilic moiety) wherein the probability ofdissociation is low. In embodiments, the irreversible covalent bond doesnot easily dissociate under normal biological conditions. Inembodiments, the irreversible covalent bond is formed through a chemicalreaction between two species (e.g., electrophilic chemical moiety andnucleophilic moiety).

“Nucleophilic” as used herein refers to a chemical group that is capableof donating electron density.

The term “K-Ras” or “KRAS” or “KRas” refers to the nucleotide sequencesor proteins of human K-Ras (e.g. UniProt P01116, human K-Ras4A (e.g.,NP_203524.1, NM_033360.3)), human K-Ras4B (e.g., NP_004976.2,NM_4985.4)), or both K-Ras4A and K-Ras4B). K-Ras is understood to playan important role in the regulation of cell proliferation. The term“K-Ras” includes both the wild-type form of the nucleotide sequences orproteins as well as any mutants thereof. In some embodiments, “K-Ras” iswild-type K-Ras. In some embodiments, “K-Ras” is one or more mutantforms. The term “K-Ras” XYZ refers to a nucleotide sequence or proteinof a mutant K-Ras wherein the Y numbered amino acid of K-Ras that has anX amino acid in the wildtype instead has a Z amino acid in the mutant(e.g. K-Ras G12C has a G in wildtype protein but a C in the K-Ras G12Cmutant protein). In some embodiments K-Ras refers to K-Ras4A andK-Ras4B. In some embodiments, K-Ras refers to K-Ras4A. In someembodiments, K-Ras refers to K-Ras4B. In embodiments K-Ras refers to aprotein having an amino acid sequence described herein.

K-Ras 4A WT Human (SEQ ID NO: 4)MTEYKLVVVG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET CLLDILDTAG QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHHYREQI KRVKDSEDVP MVLVGNKCDL PSRTVDTKQA QDLARSYGIP FIETSAKTRQ RVEDAFYTLV REIRQYRLKK ISKEEKTPGC VKIKKCIIM  K-Ras 4B WT Human (SEQ ID NO: 5)MTEYKLVVVG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET CLLDILDTAG QEEYSAMRDQ YMRTGEGFLCVFAINNTKSF EDIHHYREQI KRVKDSEDVP MVLVGNKCDLPSRTVDTKQA QDLARSYGIP FIETSAKTRQ GVDDAFYTLV REIRKHKEKM SKDGKKKKKK SKTKCVIM 

The term “K-Ras inhibitor test compound” as used herein refers to acompound that is being characterized in an assay for the ability toinhibit an activity, function, or level (e.g. amount) of K-Ras (e.g.,human K-Ras 4A and/or human K-Ras 4B) protein.

The term “signaling pathway” as used herein refers to a series ofinteractions between cellular and optionally extra-cellular components(e.g. proteins, nucleic acids, small molecules, ions, lipids) thatconveys a change in one component to one or more other components, whichin turn may convey a change to additional components, which isoptionally propagated to other signaling pathway components. Forexample, binding of a K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)with a compound as described herein may result in a change in one ormore protein-protein interactions of the K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) or interactions between the K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) and a membrane, resulting in changes incell growth, proliferation, or survival.

An amino acid residue in a protein “corresponds” to a given residue whenit occupies the same essential structural position within the protein asthe given residue. For example, a selected residue in a selected proteincorresponds to Gly 12 of Human K-Ras4A (e.g., SEQ ID NO:4) or HumanK-Ras 4B (e.g., SEQ ID NO:5) or both when the selected residue occupiesthe same essential spatial or other structural relationship as Gly 12 inHuman K-Ras4A or Human K-Ras 4B or both. In some embodiments, where aselected protein is aligned for maximum homology with the Human K-Ras4Aor Human K-Ras 4B protein, the position in the aligned selected proteinaligning with Gly 12 is said to correspond to Gly 12 (e.g., Gly 12 ofSEQ ID NO:4 or Gly 12 of SEQ ID NO:5). Instead of a primary sequencealignment, a three dimensional structural alignment can also be used,e.g., where the structure of the selected protein is aligned for maximumcorrespondence with the Human K-Ras4A or Human K-Ras 4B protein and theoverall structures compared. In this case, an amino acid that occupiesthe same essential position as Gly 12 in the structural model is said tocorrespond to the Gly 12 residue (e.g., Gly 12 of SEQ ID NO:4 or Gly 12of SEQ ID NO:5). Another example is wherein a selected residue in aselected protein corresponds to H95 of Human K-Ras 4A or 4B when theselected residue (e.g., histidine residue) occupies essential the samesequence, spatial, or other structural position within the protein asH95 in Human K-Ras 4A or 4B (e.g., H95 of SEQ ID NO:4 or H95 of SEQ IDNO:5).

The terms “unsubstituted vinyl sulfone moiety”, “unsubstituted vinylsulfonamide moiety”, “unsubstituted fluoro(C₁-C₄)alkylketone moiety”,“unsubstituted chloro(C₁-C₄)alkylketone moiety”, “unsubstitutedacrylamide moiety”, “unsubstituted disulfide moiety”, “unsubstitutedthiol moiety”, “unsubstituted phosphonate moiety”, “unsubstitutedaldehyde moiety”, “unsubstituted enone moiety”, “unsubstituteddiazomethylketone moiety”, “unsubstituted diazomethylamide moiety”,“unsubstituted cyanocyclopropyl carboxamide moiety”, “unsubstitutedepoxide moiety”, “unsubstituted epoxyketone moiety”, “unsubstitutedepoxyamide moiety”, “unsubstituted aryl aldehyde moiety”, “unsubstitutedaryl dialdehyde moiety”, “unsubstituted dialdehyde moiety”,“unsubstituted nitrogen mustard moiety”, “unsubstituted propargylmoiety”, or “unsubstituted propargylamide moiety” are used according totheir plain ordinary chemical meaning and refer to those monovalentchemical groups named having the lowest molecular weight for each suchgroup while obeying the rules of chemical valency. A substituted form ofone of the named groups (e.g., vinyl sulfone moiety) may be substitutedwith one or more of any of the substituent groups described herein(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) while obeying the rules of chemicalvalency.

II. COMPOUNDS

In an aspect is provided a compound having the formula:

Ring A is an aryl or heteroaryl.

R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B), —NHNR^(1A)R^(1B),—ONR^(1A)R^(1B), —NHC═(O)NHNR^(1A)R^(1B), —NHC(O)NR^(1A)R^(1B),—N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C), —C(O)—OR^(1C),—C(O)NR^(1A)R^(1B), —OR^(1D), —NR^(1A)SO₂R^(1D), —NR^(1A)C(O)R^(1C),—NR^(1A)C(O)OR^(1C), —NR^(1A)OR^(1C), —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹, —N₃,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted alkyl(e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered); two adjacent R¹ substituents mayoptionally be joined to form a substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

The symbol z1 is an integer from 0 to 4.

R² is independently hydrogen, —CX² ₃, —CHX² ₂, —CH₂X², —C(O)R^(2A),—C(O)OR^(2A), —C(O)NR^(2A)R^(2B), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered,2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

L¹ is a bond, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted alkylene (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted cycloalkylene (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), or

L² is a bond, —O—, —C(O)—, —C(O)O—, —OC(O)—, —S—, —SO—, —S(O)₂—, —NH—,—NHC(O)—, —C(O)NH—, —SO₂NH—, —NHSO₂—, —OC(O)NH—, —NHC(O)O—, —NHC(O)NH—,—C(O)OCH₂—, —CH₂OC(O)—, —C(O)NHCH₂—, —CH₂NHC(O)—, —CH₂NHCH₂—,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted alkylene(e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), or substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heteroalkylene(e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).

L³ is a bond, —S(O)₂—, —N(R³)—, —O—, —S—, —C(O)—, —C(O)N(R³)—,—N(R³)C(O)—, —N(R³)C(O)NH—, —NHC(O)N(R³)—, —C(O)O—, —OC(O)—, substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted alkylene (e.g.,C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted cycloalkylene (e.g.,C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted arylene (e.g., C₆-C₁₂, C₆-C₁₀, orphenylene), or substituted (e.g., substituted with a substituent group,a size-limited substituent group, or lower substituent group) orunsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered).

R³ is independently hydrogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —C(O)R^(3A),—C(O)OR^(3A), —C(O)NR^(3A)R^(3B), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered,2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

L⁴ is a bond, —S(O)₂—, —N(R⁴)—, —O—, —S—, —C(O)—, —C(O)N(R⁴)—,—N(R⁴)C(O)—, —N(R⁴)C(O)NH—, —NHC(O)N(R⁴)—, —C(O)O—, —OC(O)—, substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted alkylene (e.g.,C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted cycloalkylene (e.g.,C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkylene (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted arylene (e.g., C₆-C₁₂, C₆-C₁₀, orphenylene), or substituted (e.g., substituted with a substituent group,a size-limited substituent group, or lower substituent group) orunsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5to 9 membered, or 5 to 6 membered).

R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —C(O)R^(4A),—C(O)OR^(4A), —C(O)NR^(4A)R^(4B), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered,2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

R⁵ is independently hydrogen, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered,2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered), or E.

E is a histidine binding moiety.

Each R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(3A), R^(3B),R^(4A), and R^(4B) is independently hydrogen, —CX₃, —CN, —COOH, —CONH₂,—CHX₂, —CH₂X, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), substituted (e.g., substituted with a substituent group,a size-limited substituent group, or lower substituent group) orunsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R^(1A) andR^(1B) substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered,3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered)or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered); R^(2A) and R^(2B) substituents bondedto the same nitrogen atom may optionally be joined to form a substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heterocycloalkyl(e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered) or substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 12membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R^(3A)and R^(3B) substituents bonded to the same nitrogen atom may optionallybe joined to form a substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered,3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered)or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered); R^(4A) and R^(4B) substituents bondedto the same nitrogen atom may optionally be joined to form a substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heterocycloalkyl(e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered) or substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 12membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

Each X, X¹, X², X³, and X⁴ is independently —F, —Cl, —Br, or —I.

The symbol n1 is independently an integer from 0 to 4.

The symbols m1 and v1 are independently 1 or 2.

In embodiments, the compound has the formula:

and R¹, R², R⁵, Ring A, L¹, L³, L⁴, and z1 are as described herein.

In embodiments, the compound has the formula:

and R¹, R², E, Ring A, L¹, L³, L⁴, and z1 are as described herein.

In embodiments, the compound has the formula:

and R¹, R², E, Ring A, L¹, L³, L⁴, and z1 are as described herein.

In embodiments, the compound has the formula:

and R¹, R⁵, Ring A, L², L³, L⁴, and z1 are as described herein.

In embodiments, the compound has the formula:

and R¹, E, Ring A, L², L³, L⁴, and z1 are as described herein.

In embodiments, Ring A is aryl (e.g. C₆-C₁₂ aryl, C₆-C₁₀ aryl, or C₆aryl). In embodiments, Ring A is C₆-C₁₂ aryl. In embodiments, Ring A isC₆-C₁₀ aryl. In embodiments, Ring A is C₆ aryl. It will be understoodwhen z1 is 0, Ring A is unsubstituted (e.g., unsubstituted aryl orunsubstituted heteroaryl) in addition to the bond to L². It will beunderstood when z1 is greater than 0 (e.g., 1, 2, 3, or 4), Ring A issubstituted with one or more R¹ substituents (e.g., R¹-substituted arylor R¹-substituted heteroaryl) in addition to the bond to L².

In embodiments, Ring A is heteroaryl (e.g. 5 to 12 membered heteroaryl,5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, Ring A is 5 to 12 memberedheteroaryl. In embodiments, Ring A is 5 to 10 membered heteroaryl. Inembodiments, Ring A is 5 to 9 membered heteroaryl. In embodiments, RingA is 5 to 6 membered heteroaryl.

In embodiments, Ring A is naphthyl. In embodiments, Ring A is biphenyl.In embodiments, Ring A is phenyl. In embodiments, Ring A is pyridyl. Inembodiments, Ring A is pyrazolyl. In embodiments, Ring A is imidazolyl.In embodiments, Ring A is oxazolyl. In embodiments, Ring A isisoxazolyl. In embodiments, Ring A is thiazolyl. In embodiments, Ring Ais furanyl. In embodiments, Ring A is pyrrolyl. In embodiments, Ring Ais thienyl.

In embodiments, Ring A is indolinyl. In embodiments, Ring A isindazolyl. In embodiments, Ring A is benzimidazolyl. In embodiments,Ring A is benzoxazolyl. In embodiments, Ring A is azaindolyl. Inembodiments, Ring A is purinyl. In embodiments, Ring A is indolyl. Inembodiments, Ring A is pyrazinyl. In embodiments, Ring A is pyrrolyl. Inembodiments, Ring A is imidazolyl. In embodiments, Ring A is pyrazolyl.In embodiments, Ring A is triazolyl. In embodiments, Ring A istetrazolyl. In embodiments, Ring A is benzofuranyl. In embodiments, RingA is indolyl. In embodiments, Ring A is benzothienyl.

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, -(Ring A)-(R¹)_(z1) has the formula:

In embodiments, R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹,—CN, —SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B), —NHNR^(1A)R^(1B),—ONR^(1A)R^(1B), —NHC═(O)NHNR^(1A)R^(1B), —NHC(O)NR^(1A)R^(1B),—N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C), —C(O)—OR^(1C),—C(O)NR^(1A)R^(1B), —OR^(1D), —NR^(1A)SO₂R^(1D), —NR^(1A)C(O)R^(1C),—NR^(1A)C(O)OR^(1C), —NR^(1A)OR^(1C), —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted alkyl(e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered); two adjacent R¹ substituents mayoptionally be joined to form a substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹,—CN, —SR^(1D), —SO₂R^(1D), —NHC(O)NR^(1A)R^(1B), —N(O)₂, —NR^(1A)R^(1B),—C(O)R^(1C), —C(O)OR^(1C), —C(O)NR^(1A)R^(1B), —OR^(1D), —OCX¹ ₃, —OCHX¹₂, —OCH₂X¹, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), substituted (e.g., substituted with a substituent group,a size-limited substituent group, or lower substituent group) orunsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCX¹ ₃, —OCHX¹ ₂, OCH₂X¹, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered,2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹,—OH, —CN, —SO₂CH₃, —NO₂, —N(CH₃)₂, —NH₂, —SH, —COOH, —OCX¹ ₃, —OCHX¹ ₂,—CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —SCH₃, or —SCH₂CH₃.

In embodiments, R¹ is —SO_(n1)R^(1D). In embodiments, R¹ is—SO_(v1)NR^(1A)R^(1B). In embodiments, R¹ is —NHNR^(1A)R^(1B). Inembodiments, R¹ is —ONR^(1A)R^(1B). In embodiments, R¹ is—NHC═(O)NHNR^(1A)R^(1B). In embodiments, R¹ is —NHC(O)NR^(1A)R^(1B). Inembodiments, R¹ is —N(O)_(m1). In embodiments, R¹ is —NR^(1A)R^(1B). Inembodiments, R¹ is —C(O)R^(1C). In embodiments, R¹ is —C(O)—OR^(1C). Inembodiments, R¹ is —C(O)NR^(1A)R^(1B). In embodiments, R¹ is —OR^(1D).In embodiments, R¹ is —NR^(1A)SO₂R^(1D). In embodiments, R¹ is—NR^(1A)C(O)R^(1C). In embodiments, R¹ is —NR^(1A)C(O)OR^(1C). Inembodiments, R¹ is —NR^(1A)OR^(1C). In embodiments, R¹ is substituted orunsubstituted C₁-C₆ alkyl. In embodiments, R¹ is substituted orunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹ issubstituted or unsubstituted C₃-C₈ cycloalkyl. In embodiments, R¹ issubstituted or unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R¹ is substituted or unsubstituted phenyl. In embodiments,R¹ is substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R¹ is independently halogen. In embodiments, R¹ isindependently —CX¹³. In embodiments, R¹ is independently —CHX¹². Inembodiments, R¹ is independently —CH₂X. In embodiments, R¹ isindependently —OH. In embodiments, R¹ is independently —SH. Inembodiments, R¹ is independently —COOH. In embodiments, R¹ isindependently —OCX¹ ₃. In embodiments, R¹ is independently —OCHX¹². Inembodiments, R¹ is independently —OCH₂X¹. In embodiments, R¹ isindependently —CH₃. In embodiments, R¹ is independently —CH₂CH₃. Inembodiments, R¹ is independently —OCH₃. In embodiments, R¹ isindependently —OCH₂CH₃. In embodiments, R¹ is independently —SCH₃. Inembodiments, R¹ is independently —SCH₂CH₃. In embodiments, R¹ isindependently —CN. In embodiments, R¹ is independently —SO₂CH₃. Inembodiments, R¹ is independently —NO₂. In embodiments, R¹ isindependently —N(CH₃)₂. In embodiments, R¹ is independently —NH(CH₃). Inembodiments, R¹ is independently —NH(unsubstituted phenyl). Inembodiments, R¹ is independently —NH(unsubstituted 5 to 6 memberedheteroaryl). In embodiments, R¹ is independently —NH₂. In embodiments,R¹ is independently unsubstituted methyl. In embodiments, R¹ isindependently unsubstituted ethyl. In embodiments, R¹ is independentlyunsubstituted propyl. In embodiments, R¹ is independently unsubstitutedn-propyl. In embodiments, R¹ is independently unsubstituted isopropyl.In embodiments, R¹ is independently unsubstituted butyl. In embodiments,R¹ is independently unsubstituted n-butyl. In embodiments, R¹ isindependently unsubstituted isobutyl. In embodiments, R¹ isindependently unsubstituted tert-butyl. In embodiments, R¹ isindependently unsubstituted pentyl. In embodiments, R¹ is independentlyunsubstituted hexyl. In embodiments, R¹ is independently unsubstitutedheptyl. In embodiments, R¹ is independently unsubstituted octyl. Inembodiments, R¹ is independently —F. In embodiments, R¹ is independently—Cl. In embodiments, R¹ is independently —Br. In embodiments, R¹ isindependently —I. In embodiments, R¹ is independently unsubstitutedmethoxy. In embodiments, R¹ is independently unsubstituted ethoxy. Inembodiments, R¹ is independently —CF₃. In embodiments, R¹ isindependently —CCl₃. In embodiments, R¹ is an unsubstituted phenyl. Inembodiments, R¹ is an unsubstituted pyridyl. In embodiments, R¹ isindependently halogen. In embodiments, R¹ is independently —CONH₂. Inembodiments, R¹ is independently —SO₃H. In embodiments, R¹ isindependently —SO₄H. In embodiments, R¹ is independently —SO₂NH₂. Inembodiments, R¹ is independently —NHNH₂. In embodiments, R¹ isindependently —ONH₂. In embodiments, R¹ is independently —NHC(O)NHNH₂.In embodiments, R¹ is independently —NHC(O)NH₂. In embodiments, R¹ isindependently —NHSO₂H. In embodiments, R¹ is independently —NHC(O)H. Inembodiments, R¹ is independently —NHC(O)OH. In embodiments, R¹ isindependently —NHOH. In embodiments, R¹ is independently —OCOCH₃. Inembodiments, R¹ is independently —NR^(1A)R^(1B). In embodiments, R¹ isindependently —NHR^(1B), wherein R^(1B) is a substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. Inembodiments, R¹ is independently —NHR^(1B), wherein R^(1B) is anunsubstituted aryl or unsubstituted heteroaryl. In embodiments, R¹ isindependently

In embodiments, R¹ is independently substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted alkyl. In embodiments, R¹ isindependently substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) alkyl. Inembodiments, R¹ is independently unsubstituted alkyl. In embodiments, R¹is independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂). In embodiments, R¹ is independently substituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R¹ isindependently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).

In embodiments, R¹ is independently substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl. In embodiments, R¹ isindependently substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) heteroalkyl.In embodiments, R¹ is independently unsubstituted heteroalkyl. Inembodiments, R¹ is independently substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered). In embodiments, R¹ is independentlysubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R¹ isindependently an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).

In embodiments, R¹ is independently substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl. In embodiments, R¹ isindependently substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) cycloalkyl.In embodiments, R¹ is independently an unsubstituted cycloalkyl. Inembodiments, R¹ is independently substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, R¹ isindependently substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆). In embodiments, R¹ is independently unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆).

In embodiments, R¹ is independently substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl. In embodiments, R¹is independently substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group)heterocycloalkyl. In embodiments, R¹ is independently an unsubstitutedheterocycloalkyl. In embodiments, R¹ is independently substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R¹ is independently substituted heterocycloalkyl (e.g., 3 to 8 membered,3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).In embodiments, R¹ an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

In embodiments, R¹ is independently substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl. In embodiments, R¹ isindependently substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) aryl. Inembodiments, R¹ is independently an unsubstituted aryl. In embodiments,R¹ is independently substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl). In embodiments, R¹ is independently substituted aryl (e.g.,C₆-C₁₀ or phenyl). In embodiments, R¹ is independently an unsubstitutedaryl (e.g., C₆-C₁₀ or phenyl).

In embodiments, R¹ is independently substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroaryl. In embodiments, R¹ isindependently substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) heteroaryl.In embodiments, R¹ is independently an unsubstituted heteroaryl. Inembodiments, R¹ is independently substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R¹ is independently substituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R¹ isindependently an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹,—CN, —SR^(1D), —SO₂RD, —NR^(1A)R^(1B), —OR^(1D), unsubstituted C₁-C₆alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C₃-C₆cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl,unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SO₂CH₃, —NHPh (Ph=phenyl), —CH₃, or —CH₂CH₃. In embodiments, R¹ isindependently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN, —SR^(1D), —N(O)₂,—SO₂RD, —NR^(1A)R^(1B), —OR^(1D), unsubstituted C₁-C₆ alkyl,unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C₃-C₆cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl,unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹₃, —OCHX¹ ₂, —OCH₂X¹, —CN, —N(O)₂, —SO₂CH₃, —N(CH₃)₂, —OCH₃, —OCH₂CH₃,—CH₃, or —CH₂CH₃.

In embodiments, two adjacent R¹ substituents may optionally be joined toform a substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, two adjacent R¹ substituents may optionally be joined toform a substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted cycloalkyl. In embodiments, two adjacent R¹ substituentsmay optionally be joined to form a substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) cycloalkyl. In embodiments, two adjacent R¹substituents may optionally be joined to form an unsubstitutedcycloalkyl. In embodiments, two adjacent R¹ substituents may optionallybe joined to form a substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, two adjacent R¹substituents may optionally be joined to form a substituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, two adjacent R¹substituents may optionally be joined to form an unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆).

In embodiments, two adjacent R¹ substituents may optionally be joined toform a substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heterocycloalkyl. In embodiments, two adjacent R¹substituents may optionally be joined to form a substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) heterocycloalkyl. In embodiments, twoadjacent R¹ substituents may optionally be joined to form anunsubstituted heterocycloalkyl. In embodiments, two adjacent R¹substituents may optionally be joined to form a substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,two adjacent R¹ substituents may optionally be joined to form asubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, twoadjacent R¹ substituents may optionally be joined to form anunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).

In embodiments, two adjacent R¹ substituents may optionally be joined toform a substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted aryl. In embodiments, two adjacent R¹ substituents mayoptionally be joined to form a substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) aryl. In embodiments, two adjacent R¹ substituentsmay optionally be joined to form an unsubstituted aryl. In embodiments,two adjacent R¹ substituents may optionally be joined to form asubstituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl). Inembodiments, two adjacent R¹ substituents may optionally be joined toform a substituted aryl (e.g., C₆-C₁₀ or phenyl). In embodiments, twoadjacent R¹ substituents may optionally be joined to form anunsubstituted aryl (e.g., C₆-C₁₀ or phenyl).

In embodiments, two adjacent R¹ substituents may optionally be joined toform a substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl. In embodiments, two adjacent R¹ substituentsmay optionally be joined to form a substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) heteroaryl. In embodiments, two adjacent R¹substituents may optionally be joined to form an unsubstitutedheteroaryl. In embodiments, two adjacent R¹ substituents may optionallybe joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, twoadjacent R¹ substituents may optionally be joined to form a substitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). In embodiments, two adjacent R¹ substituents may optionallybe joined to form an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5to 9 membered, or 5 to 6 membered).

In embodiments, each R^(1A), R^(1B), R^(1C), and R^(1D) is independentlyhydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted alkyl (e.g., C₁-C₂₀,C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered,2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, each R^(1A), R^(1B),R^(1C), and R^(1D) is independently hydrogen. In embodiments, eachR^(1A), R^(1B), R^(1C), and R^(1D) is independently —CX₃. Inembodiments, each R^(1A), R^(1B), R^(1C), and R^(1D) is independently—CN. In embodiments, each R^(1A), R^(1B), R^(1C), and R^(1D) isindependently —COOH. In embodiments, each R^(1A), R^(1B), R^(1C), andR^(1D) is independently —CONH₂. In embodiments, each R^(1A), R^(1B),R^(1C), and R^(1D) is independently —CHX₂. In embodiments, each R^(1A),R^(1B), R^(1C), and R^(1D) is independently —CH₂X. In embodiments, eachR^(1A), R^(1B), R^(1C), and R^(1D) is independently —CH₃. Inembodiments, each R^(1A), R^(1B), R^(1C), and R^(1D) is independently—CH₂CH₃.

In embodiments, each R^(1A), R^(1B), R^(1C), and R^(1D) is independentlyhydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X, unsubstituted alkyl(e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered,3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R^(1A) and R^(1B) substituents bonded to the samenitrogen atom may optionally be joined to form a substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to5 membered, or 5 to 6 membered) or substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(1A) and R^(1B) substituents bonded to the same nitrogen atom mayoptionally be joined to independently form an unsubstitutedheterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, X is independently —F.In embodiments, X is independently —Cl. In embodiments, X isindependently —Br. In embodiments, X is independently —I.

In embodiments, z1 is 0. In embodiments, z1 is 1. In embodiments, z1 is2. In embodiments, z1 is 3. In embodiments, z1 is 4. In embodiments, X¹is independently —F. In embodiments, X¹ is independently —Cl. Inembodiments, X¹ is independently —Br. In embodiments, X¹ isindependently —I. In embodiments, n1 is independently 0. In embodiments,n1 is independently 1. In embodiments, n1 is independently 2. Inembodiments, n1 is independently 3. In embodiments, n1 is independently4. In embodiments, m1 is independently 1. In embodiments, m1 isindependently 2. In embodiments, v1 is independently 1. In embodiments,v1 is independently 2.

In embodiments, the compound has the formula:

and R², R⁵, L¹, L³, and L⁴ are as described herein. R^(1.1), R^(1.2),R^(1.3), R^(1.4), and R^(1.5) are each independently R¹ at a fixedposition (e.g., non-floating as shown in the formula described herein)and may independently be any R¹ substituent.

In embodiments, the compound has the formula:

and R^(1.2), R^(1.3), R², R⁵, L¹, L³, and L⁴ are as described herein.

In embodiments, the compound has the formula:

and R², R⁵, L³, and L⁴ are as described herein.

In embodiments, the compound has the formula:

and R⁵, L³, and L⁴ are as described herein.

In embodiments, the compound has the formula:

and R⁵, L², L³, and L⁴ are as described herein. R^(1.1), R^(1.2),R^(1.3), R^(1.4), and R^(1.5) are each independently R¹ at a fixedposition (e.g., non-floating as shown in the formula described herein)and may independently be any R¹ substituent.

In embodiments, the compound has the formula:

and R¹, R⁵, L², L³, and L⁴ are as described herein.

In embodiments, the compound has the formula:

and R⁵, L³, and L⁴ are as described herein.

In embodiments, the compound has the formula:

and R², R⁵, L¹, L³, and L⁴ are as described herein. R^(1.1), R^(1.2),R^(1.3), R^(1.4), and R^(1.5) are each independently R¹ at a fixedposition (e.g., non-floating as shown in the formula described herein)and may independently be any R¹ substituent.

In embodiments, the compound has the formula:

and R⁵, L², L³, and L⁴ are as described herein. R^(1.1), R^(1.2),R^(1.3), R^(1.4), and R^(1.5) are each independently R¹ at a fixedposition (e.g., non-floating as shown in the formula described herein)and may independently be any R¹ substituent.

In embodiments, the compound has the formula:

and R⁵, Ring A, L², L³, and L⁴ are as described herein. R^(1.1),R^(1.2), R^(1.3), R^(1.4), and R^(1.5) are each independently R¹ at afixed position (e.g., non-floating as shown in the formula describedherein) and may independently be any R¹ substituent.

In embodiments, the compound has the formula:

and R⁵, Ring A, L², L³, and L⁴ are as described herein. R^(1.1),R^(1.2), R^(1.3), R^(1.4), and R^(1.5) are each independently R¹ at afixed position (e.g., non-floating as shown in the formula describedherein) and may independently be any R¹ substituent. W¹ is —N═ or—C(R^(1.4))=. In embodiments, W¹ is —N═. In embodiments, W¹ is—C(R^(1.4))═. In embodiments, W¹ is —CH═. W² is —N═ or —C(R^(1.2))=. Inembodiments, W² is —N═. In embodiments, W² is —C(R^(1.2))=. Inembodiments, W² is —CH═. W³ is —N═ or —CH═. In embodiments, W³ is —N═.In embodiments, W³ is —CH═.

In embodiments, the compound has the formula:

and W¹, W², W³, R⁵, L³, and L⁴ are as described herein. R^(1.1),R^(1.2), R^(1.3), R^(1.4), and R^(1.5) are each independently R¹ at afixed position (e.g., non-floating as shown in the formula describedherein) and may independently be any R¹ substituent.

In embodiments, the compound has the formula:

and W¹, W², and W³ are as described herein. R^(1.1), R^(1.2), R^(1.3),R^(1.4), and R^(1.5) are each independently R¹ at a fixed position(e.g., non-floating as shown in the formula described herein) and mayindependently be any R¹ substituent.

In embodiments, the compound has the formula:

and R⁵, Ring A, L², L³, and L⁴ are as described herein. R^(1.1),R^(1.2), R^(1.3), R^(1.4), and R^(1.5) are each independently R¹ at afixed position (e.g., non-floating as shown in the formula describedherein) and may independently be any R¹ substituent.

In embodiments, the compound has the formula:

and W¹, W², R⁵, L³, and L⁴ are as described herein. R^(1.1), R^(1.2),R^(1.3), R^(1.4), and R^(1.5) are each independently R¹ at a fixedposition (e.g., non-floating as shown in the formula described herein)and may independently be any R¹ substituent.

In embodiments, the compound has the formula:

and W¹ and W² are as described herein. R^(1.1), R^(1.2), R^(1.3),R^(1.4), and R^(1.5) are each independently R¹ at a fixed position(e.g., non-floating as shown in the formula described herein) and mayindependently be any R¹ substituent.

In embodiments, the compound has the formula:

and R⁵, Ring A, L², L³, and L⁴ are as described herein. R^(1.1),R^(1.2), R^(1.3), R^(1.4), and R^(1.5) are each independently R¹ at afixed position (e.g., non-floating as shown in the formula describedherein) and may independently be any R¹ substituent.

In embodiments, the compound has the formula:

and R⁵, L³, and L⁴ are as described herein. R^(1.1), R^(1.2), R^(1.3),R^(1.4), and R^(1.5) are each independently R¹ at a fixed position(e.g., non-floating as shown in the formula described herein) and mayindependently be any R¹ substituent.

In embodiments, the compound has the formula:

R^(1.1), R^(1.2), R^(1.3), R^(1.4), and R^(1.5) are each independentlyR¹ at a fixed position (e.g., non-floating as shown in the formuladescribed herein) and may independently be any R¹ substituent.

In embodiments, the compound has the formula:

and R⁵, Ring A, L², L³, and L⁴ are as described herein. R^(1.1),R^(1.2), R^(1.3), R^(1.4), and R^(1.5) are each independently R¹ at afixed position (e.g., non-floating as shown in the formula describedherein) and may independently be any R¹ substituent.

In embodiments, the compound has the formula:

and R⁵, L³, and L⁴ are as described herein. R^(1.2), R^(1.2), R^(1.3),R^(1.4), and R^(1.5) are each independently R¹ at a fixed position(e.g., non-floating as shown in the formula described herein) and mayindependently be any R¹ substituent.

In embodiments, the compound has the formula:

R^(1.1), R^(1.2), R^(1.3), R^(1.4), and R^(1.5) are each independentlyR¹ at a fixed position (e.g., non-floating as shown in the formuladescribed herein) and may independently be any R¹ substituent.

In embodiments, the compound has the formula:

and R², R⁵, L, L³, and L⁴ are as described herein. R^(1.1), R^(1.2),R^(1.3), R^(1.4), and R^(1.5) are each independently R¹ at a fixedposition (e.g., non-floating as shown in the formula described herein)and may independently be any R¹ substituent.

In embodiments, the compound has the formula:

and R², R⁵, L¹, L³, and L⁴ are as described herein. R^(1.1), R^(1.2),R^(1.4), and R^(1.5) are each independently R¹ at a fixed position(e.g., non-floating as shown in the formula described herein) and mayindependently be any R¹ substituent.

In embodiments, the compound has the formula:

and R², R⁵, L¹, L³, and L⁴ are as described herein. R^(1.1), R^(1.2),R^(1.3), and R^(1.5) are each independently R¹ at a fixed position(e.g., non-floating as shown in the formula described herein) and mayindependently be any R¹ substituent.

In embodiments, the compound has the formula:

and R², R⁵, L¹, L³, and L⁴ are as described herein. R^(1.1), R^(1.2),R^(1.3), and R^(1.4) are each independently R¹ at a fixed position(e.g., non-floating as shown in the formula described herein) and mayindependently be any R¹ substituent.

R^(1.1) is independently hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂,—CH₂X^(1.1), —CN, —SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B),—NHNR^(1A)R^(1B), —ONR^(1A)R^(1B), —NHC═(O)NHNR^(1A)R^(1B),—NHC(O)NR^(1A)R^(1B), —N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C),—C(O)—OR^(1C), —C(O)NR^(1A)R^(1B), —OR^(1D),—NR^(1A)SO₂R^(1D)—NR^(1A)C(O)R^(1C), —NR^(1A)C(O)OR^(1C),—NR^(1A)OR^(1C), —OCX^(1.1) ₃, —OCHX^(1.1) ₂, —OCH₂X^(1.1), substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted alkyl (e.g., C₁-C₂₀,C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered,2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(1.1) isindependently hydrogen.

In embodiments, R^(1.1) is independently halogen, —CX^(1.1) ₃,—CHX^(1.1) ₂, —CH₂X^(1.1), —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCX^(1.1) ₃, —OCHX^(1.1) ₂, OCH₂X^(1.1),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted alkyl(e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R¹ is independently halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂,—CH₂X^(1.1), —OH, —CN, —SO₂CH₃, —NO₂, —N(CH₃)₂, —NH₂, —SH, —CO OH,—OCX^(1.1) ₃, —OCHX^(1.1) ₂, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —SCH₃, or—SCH₂CH₃.

In embodiments, R¹ is substituted or unsubstituted C₁-C₆ alkyl. Inembodiments, R¹ is substituted or unsubstituted 2 to 6 memberedheteroalkyl. In embodiments, R¹ is substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R^(1.1) is substituted or unsubstituted 3 to6 membered heterocycloalkyl. In embodiments, R^(1.1) is substituted orunsubstituted phenyl. In embodiments, R^(1.1) is substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R^(1.1) isindependently halogen. In embodiments, R^(1.1) is independently—CX^(1.1) ₃. In embodiments, R^(1.1) is independently —CHX^(1.1) ₂. Inembodiments, R^(1.1) is independently —CH₂X^(1.1). In embodiments,R^(1.1) is independently —OH. In embodiments, R^(1.1) is independently—SH. In embodiments, R^(1.1) is independently —COOH. In embodiments,R^(1.1) is independently —OCX^(1.1) ₃. In embodiments, R^(1.1) isindependently —OCHX^(1.1) ₂. In embodiments, R^(1.1) is independently—OCH₂X^(1.1). In embodiments, R^(1.1) is independently —CH₃. Inembodiments, R^(1.1) is independently —CH₂CH₃. In embodiments, R^(1.1)is independently —OCH₃. In embodiments, R^(1.1) is independently—OCH₂CH₃. In embodiments, R^(1.1) is independently —SCH₃. Inembodiments, R^(1.1) is independently —SCH₂CH₃. In embodiments, R^(1.1)is independently —CN. In embodiments, R^(1.1) is independently —SO₂CH₃.In embodiments, R^(1.1) is independently —NO₂. In embodiments, R^(1.1)is independently —N(CH₃)₂. In embodiments, R^(1.1) is independently—NH(CH₃). In embodiments, R^(1.1) is independently —NH(unsubstitutedphenyl). In embodiments, R^(1.1) is independently —NH(unsubstituted 5 to6 membered heteroaryl). In embodiments, R^(1.1) is independently —NH₂.In embodiments, R^(1.1) is independently unsubstituted methyl. Inembodiments, R^(1.1) is independently unsubstituted ethyl. Inembodiments, R^(1.1) is independently unsubstituted propyl. Inembodiments, R^(1.1) is independently unsubstituted n-propyl. Inembodiments, R^(1.1) is independently unsubstituted isopropyl. Inembodiments, R^(1.1) is independently unsubstituted butyl. Inembodiments, R^(1.1) is independently unsubstituted n-butyl. Inembodiments, R^(1.1) is independently unsubstituted isobutyl. Inembodiments, R^(1.1) is independently unsubstituted tert-butyl. Inembodiments, R^(1.1) is independently unsubstituted pentyl. Inembodiments, R^(1.1) is independently unsubstituted hexyl. Inembodiments, R^(1.1) is independently unsubstituted heptyl. Inembodiments, R^(1.1) is independently unsubstituted octyl. Inembodiments, R^(1.1) is independently —F. In embodiments, R^(1.1) isindependently —Cl. In embodiments, R^(1.1) is independently —Br. Inembodiments, R^(1.1) is independently —I. In embodiments, R^(1.1) isindependently unsubstituted methoxy. In embodiments, R^(1.1) isindependently unsubstituted ethoxy. In embodiments, R^(1.1) isindependently —CF₃. In embodiments, R^(1.1) is independently —CCl₃. Inembodiments, R^(1.1) is an unsubstituted phenyl. In embodiments, R^(1.1)is an unsubstituted pyridyl. In embodiments, R^(1.1) is independentlyhalogen. In embodiments, R^(1.1) is independently —CONH₂. Inembodiments, R^(1.1) is independently —SO₃H. In embodiments, R^(1.1) isindependently —SO₄H. In embodiments, R^(1.1) is independently —SO₂NH₂.In embodiments, R^(1.1) is independently —NHNH₂. In embodiments, R^(1.1)is independently —ONH₂. In embodiments, R^(1.1) is independently—NHC(O)NHNH₂. In embodiments, R^(1.1) is independently —NHC(O)NH₂. Inembodiments, R^(1.1) is independently —NHSO₂H. In embodiments, R^(1.1)is independently —NHC(O)H. In embodiments, R^(1.1) is independently—NHC(O)OH. In embodiments, R^(1.1) is independently —NHOH. Inembodiments, X¹ is independently —F. In embodiments, X¹ is independently—Cl. In embodiments, X¹ is independently —Br. In embodiments, X¹¹ isindependently —I.

R^(1.2) is independently hydrogen, halogen, —CX^(1.2) ₃, —CHX^(1.2) ₂,—CH₂X^(1.2), —CN, —SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B),—NHNR^(1A)R^(1B), —ONR^(1A)R^(1B), —NHC═(O)NHNR^(1A)R^(1B),—NHC(O)NR^(1A)R^(1B), —N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C),—C(O)—OR^(1C), —C(O)NR^(1A)R^(1B), —OR^(1D), —NR^(1A)SO₂R^(1D),—NR^(1A)C(O)R^(1C), —NR^(1A)C(O)OR^(1C), —NR^(1A)OR^(1C), —OCX^(1.2) ₃,—OCHX^(1.2) ₂, —OCH₂X^(1.2), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered,2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(1.2) isindependently hydrogen.

In embodiments, R^(1.2) is independently halogen, —CX^(1.2) ₃,—CHX^(1.2) ₂, —CH₂X^(1.2), —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCX^(1.2) ₃, —OCHX^(1.2) ₂, OCH₂X^(1.2),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted alkyl(e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(1.2) is independently halogen, —CX^(1.2) ₃,—CHX^(1.2) ₂, —CH₂X^(1.2), —OH, —CN, —SO₂CH₃, —NO₂, —N(CH₃)₂, —NH₂, —SH,—CO OH, —OCX^(1.2) ₃, —OCHX^(1.2) ₂, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃,—SCH₃, or —SCH₂CH₃.

In embodiments, R^(1.2) is substituted or unsubstituted C₁-C₆ alkyl. Inembodiments, R^(1.2) is substituted or unsubstituted 2 to 6 memberedheteroalkyl. In embodiments, R^(1.2) is substituted or unsubstitutedC₃-C₈ cycloalkyl. In embodiments, R^(1.2) is substituted orunsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R^(1.2)is substituted or unsubstituted phenyl. In embodiments, R^(1.2) issubstituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments,R^(1.2) is independently halogen. In embodiments, R^(1.2) isindependently —CX¹-2₃. In embodiments, R^(1.2) is independently—CHX^(1.2) ₂. In embodiments, R^(1.2) is independently —CH₂X^(1.2). Inembodiments, R^(1.2) is independently —OH. In embodiments, R^(1.2) isindependently —SH. In embodiments, R¹² is independently —COOH. Inembodiments, R^(1.2) is independently —OCX^(1.2) ₃. In embodiments, R¹²is independently —OCHX^(1.2) ₂. In embodiments, R^(1.2) is independently—OCH₂X^(1.2). In embodiments, R^(1.2) is independently —CH₃. Inembodiments, R^(1.2) is independently —CH₂CH₃. In embodiments, R^(1.2)is independently —OCH₃. In embodiments, R¹² is independently —OCH₂CH₃.In embodiments, R^(1.2) is independently —SCH₃. In embodiments, R^(1.2)is independently —SCH₂CH₃. In embodiments, R^(1.2) is independently —CN.In embodiments, R^(1.2) is independently —SO₂CH₃. In embodiments,R^(1.2) is independently —NO₂. In embodiments, R^(1.2) is independently—N(CH₃)₂. In embodiments, R^(1.2) is independently —NH(CH₃). Inembodiments, R^(1.2) is independently —NH(unsubstituted phenyl). Inembodiments, R^(1.2) is independently —NH(unsubstituted 5 to 6 memberedheteroaryl). In embodiments, R^(1.2) is independently —NH₂. Inembodiments, R^(1.2) is independently unsubstituted methyl. Inembodiments, R^(1.2) is independently unsubstituted ethyl. Inembodiments, R^(1.2) is independently unsubstituted propyl. Inembodiments, R^(1.2) is independently unsubstituted n-propyl. Inembodiments, R^(1.2) is independently unsubstituted isopropyl. Inembodiments, R^(1.2) is independently unsubstituted butyl. Inembodiments, R^(1.2) is independently unsubstituted n-butyl. Inembodiments, R^(1.2) is independently unsubstituted isobutyl. Inembodiments, R^(1.2) is independently unsubstituted tert-butyl. Inembodiments, R^(1.2) is independently unsubstituted pentyl. Inembodiments, R^(1.2) is independently unsubstituted hexyl. Inembodiments, R^(1.2) is independently unsubstituted heptyl. Inembodiments, R^(1.2) is independently unsubstituted octyl. Inembodiments, R^(1.2) is independently —F. In embodiments, R^(1.2) isindependently —Cl. In embodiments, R^(1.2) is independently —Br. Inembodiments, R^(1.2) is independently —I. In embodiments, R^(1.2) isindependently unsubstituted methoxy. In embodiments, R^(1.2) isindependently unsubstituted ethoxy. In embodiments, R^(1.2) isindependently —CF₃. In embodiments, R^(1.2) is independently —CCl₃. Inembodiments, R^(1.2) is an unsubstituted phenyl. In embodiments, R^(1.2)is an unsubstituted pyridyl. In embodiments, R^(1.2) is independentlyhalogen. In embodiments, R^(1.2) is independently —CONH₂. Inembodiments, R^(1.2) is independently —SO₃H. In embodiments, R^(1.2) isindependently —SO₄H. In embodiments, R^(1.2) is independently —SO₂NH₂.In embodiments, R^(1.2) is independently —NHNH₂. In embodiments, R^(1.2)is independently —ONH₂. In embodiments, R^(1.2) is independently—NHC(O)NHNH₂. In embodiments, R^(1.2) is independently —NHC(O)NH₂. Inembodiments, R^(1.2) is independently —NHSO₂H. In embodiments, R^(1.2)is independently —NHC(O)H. In embodiments, R^(1.2) is independently—NHC(O)OH. In embodiments, R^(1.2) is independently —NHOH. Inembodiments, X^(1.2) is independently —F. In embodiments, X^(1.2) isindependently —Cl. In embodiments, X^(1.2) is independently —Br. Inembodiments, X^(1.2) is independently —I.

R^(1.3) is independently hydrogen, halogen, —CX^(1.3) ₃, —CHX^(1.3) ₂,—CH₂X^(1.3), —CN, —SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B),—NHNR^(1A)R^(1B), —ONR^(1A)R^(1B), —NHC═(O)NHNR^(1A)R^(1B),—NHC(O)NR^(1A)R^(1B), —N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C),—C(O)—OR^(1C), —C(O)NR^(1A)R^(1B), —OR^(1D),—NR^(1A)SO₂R^(1D)—NR^(1A)C(O)R^(1C), —NR^(1A)C(O)OR^(1C),—NR^(1A)OR^(1C), —OCX^(1.3) ₃, —OCHX^(1.3) ₂, —OCH₂X^(1.3), substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted alkyl (e.g., C₁-C₂₀,C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered,2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(1.3) isindependently hydrogen.

In embodiments, R^(1.3) is independently halogen, —CX^(1.3) ₃,—CHX^(1.3) ₂, —CH₂X^(1.3), —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCX^(1.3) ₃, —OCHX^(1.3) ₂, OCH₂X^(1.3),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted alkyl(e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(1.3) is independently halogen, —CX^(1.3) ₃,—CHX^(1.3) ₂, —CH₂X^(1.3), —OH, —CN, —SO₂CH₃, —NO₂, —N(CH₃)₂, —NH₂, —SH,—CO OH, —OCX^(1.3) ₃, —OCHX^(1.3) ₂, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃,—SCH₃, or —SCH₂CH₃.

In embodiments, R^(1.3) is substituted or unsubstituted C₁-C₆ alkyl. Inembodiments, R^(1.3) is substituted or unsubstituted 2 to 6 memberedheteroalkyl. In embodiments, R¹³ is substituted or unsubstituted C₃-C₈cycloalkyl. In embodiments, R^(1.3) is substituted or unsubstituted 3 to6 membered heterocycloalkyl. In embodiments, R^(1.3) is substituted orunsubstituted phenyl. In embodiments, R^(1.3) is substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R^(1.3) isindependently halogen. In embodiments, R^(1.3) is independently—CX^(1.3) ₃. In embodiments, R^(1.3) is independently —CHX^(1.3) ₂. Inembodiments, R^(1.3) is independently —CH₂X^(1.3). In embodiments,R^(1.3) is independently —OH. In embodiments, R^(1.3) is independently—SH. In embodiments, R^(1.3) is independently —COOH. In embodiments,R^(1.3) is independently —OCX^(1.3) ₃. In embodiments, R^(1.3) isindependently —OCHX^(1.3) ₂. In embodiments, R^(1.3) is independently—OCH₂X^(1.3). In embodiments, R^(1.3) is independently —CH₃. Inembodiments, R^(1.3) is independently —CH₂CH₃. In embodiments, R^(1.3)is independently —OCH₃. In embodiments, R^(1.3) is independently—OCH₂CH₃. In embodiments, R^(1.3) is independently —SCH₃. Inembodiments, R^(1.3) is independently —SCH₂CH₃. In embodiments, R^(1.3)is independently —CN. In embodiments, R^(1.3) is independently —SO₂CH₃.In embodiments, R^(1.3) is independently —NO₂. In embodiments, R^(1.3)is independently —N(CH₃)₂. In embodiments, R^(1.3) is independently—NH(CH₃). In embodiments, R^(1.3) is independently —NH(unsubstitutedphenyl). In embodiments, R^(1.3) is independently —NH(unsubstituted 5 to6 membered heteroaryl). In embodiments, R^(1.3) is independently —NH₂.In embodiments, R^(1.3) is independently unsubstituted methyl. Inembodiments, R^(1.3) is independently unsubstituted ethyl. Inembodiments, R^(1.3) is independently unsubstituted propyl. Inembodiments, R^(1.3) is independently unsubstituted n-propyl. Inembodiments, R^(1.3) is independently unsubstituted isopropyl. Inembodiments, R^(1.3) is independently unsubstituted butyl. Inembodiments, R^(1.3) is independently unsubstituted n-butyl. Inembodiments, R^(1.3) is independently unsubstituted isobutyl. Inembodiments, R^(1.3) is independently unsubstituted tert-butyl. Inembodiments, R^(1.3) is independently unsubstituted pentyl. Inembodiments, R^(1.3) is independently unsubstituted hexyl. Inembodiments, R^(1.3) is independently unsubstituted heptyl. Inembodiments, R^(1.3) is independently unsubstituted octyl. Inembodiments, R^(1.3) is independently —F. In embodiments, R^(1.3) isindependently —Cl. In embodiments, R^(1.3) is independently —Br. Inembodiments, R^(1.3) is independently —I. In embodiments, R^(1.3) isindependently unsubstituted methoxy. In embodiments, R^(1.3) isindependently unsubstituted ethoxy. In embodiments, R^(1.3) isindependently —CF₃. In embodiments, R^(1.3) is independently —CCl₃. Inembodiments, R^(1.3) is an unsubstituted phenyl. In embodiments, R^(1.3)is an unsubstituted pyridyl. In embodiments, R^(1.3) is independentlyhalogen. In embodiments, R^(1.3) is independently —CONH₂. Inembodiments, R^(1.3) is independently —SO₃H. In embodiments, R^(1.3) isindependently —SO₄H. In embodiments, R^(1.3) is independently —SO₂NH₂.In embodiments, R^(1.3) is independently —NHNH₂. In embodiments, R^(1.3)is independently —ONH₂. In embodiments, R^(1.3) is independently—NHC(O)NHNH₂. In embodiments, R^(1.3) is independently —NHC(O)NH₂. Inembodiments, R^(1.3) is independently —NHSO₂H. In embodiments, R^(1.3)is independently —NHC(O)H. In embodiments, R^(1.3) is independently—NHC(O)OH. In embodiments, R^(1.3) is independently —NHOH. Inembodiments, X^(1.3) is independently —F. In embodiments, X^(1.3) isindependently —Cl. In embodiments, X^(1.3) is independently —Br. Inembodiments, X^(1.3) is independently —I.

R^(1.4) is independently hydrogen, halogen, —CX^(1.4) ₃, —CHX^(1.4) ₂,—CH₂X^(1.4), —CN, —SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B),—NHNR^(1A)R^(1B), —ONR^(1A)R^(1B), —NHC═(O)NHNR^(1A)R^(1B),—NHC(O)NR^(1A)R^(1B), —N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C),—C(O)—OR^(1C), —C(O)NR^(1A)R^(1B), —OR^(1D), —NR^(1A)SO₂R^(1D),—NR^(1A)C(O)R^(1C), —NR^(1A)C(O)OR^(1C), —NR^(1A)OR^(1C), —OCX^(1.4) ₃,—OCHX^(1.4) ₂, —OCH₂X^(1.4), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered,2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(1.4) isindependently hydrogen.

In embodiments, R^(1.4) is independently halogen, —CX^(1.4) ₃,—CHX^(1.4) ₂, —CH₂X^(1.4), —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCX^(1.4) ₃, —OCHX^(1.4) ₂, OCH₂X^(1.4),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted alkyl(e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(1.4) is independently halogen, —CX^(1.4) ₃,—CHX^(1.4) ₂, —CH₂X^(1.4), —OH, —CN, —SO₂CH₃, —NO₂, —N(CH₃)₂, —NH₂, —SH,—CO OH, —OCX^(1.4) ₃, —OCHX^(1.4) ₂, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃,—SCH₃, or —SCH₂CH₃.

In embodiments, R^(1.4) is substituted or unsubstituted C₁-C₆ alkyl. Inembodiments, R^(1.4) is substituted or unsubstituted 2 to 6 memberedheteroalkyl. In embodiments, R^(1.4) is substituted or unsubstitutedC₃-C₈ cycloalkyl. In embodiments, R^(1.4) is substituted orunsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R^(1.4)is substituted or unsubstituted phenyl. In embodiments, R^(1.4) issubstituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments,R^(1.4) is independently halogen. In embodiments, R^(1.4) isindependently —CX^(1.4) ₃. In embodiments, R^(1.4) is independently—CHX^(1.4) ₂. In embodiments, R^(1.4) is independently —CH₂X^(1.4). Inembodiments, R^(1.4) is independently —OH. In embodiments, R^(1.4) isindependently —SH. In embodiments, R^(1.4) is independently —COOH. Inembodiments, R^(1.4) is independently —OCX^(1.4) ₃. In embodiments,R^(1.4) is independently —OCHX^(1.4) ₂. In embodiments, R^(1.4) isindependently —OCH₂X^(1.4). In embodiments, R^(1.4) is independently—CH₃. In embodiments, R^(1.4) is independently —CH₂CH₃. In embodiments,R^(1.4) is independently —OCH₃. In embodiments, R^(1.4) is independently—OCH₂CH₃. In embodiments, R^(1.4) is independently —SCH₃. Inembodiments, R^(1.4) is independently —SCH₂CH₃. In embodiments, R^(1.4)is independently —CN. In embodiments, R^(1.4) is independently —SO₂CH₃.In embodiments, R^(1.4) is independently —NO₂. In embodiments, R^(1.4)is independently —N(CH₃)₂. In embodiments, R^(1.4) is independently—NH(CH₃). In embodiments, R^(1.4) is independently —NH(unsubstitutedphenyl). In embodiments, R^(1.4) is independently —NH(unsubstituted 5 to6 membered heteroaryl). In embodiments, R^(1.4) is independently —NH₂.In embodiments, R^(1.4) is independently unsubstituted methyl. Inembodiments, R^(1.4) is independently unsubstituted ethyl. Inembodiments, R^(1.4) is independently unsubstituted propyl. Inembodiments, R^(1.4) is independently unsubstituted n-propyl. Inembodiments, R^(1.4) is independently unsubstituted isopropyl. Inembodiments, R^(1.4) is independently unsubstituted butyl. Inembodiments, R^(1.4) is independently unsubstituted n-butyl. Inembodiments, R^(1.4) is independently unsubstituted isobutyl. Inembodiments, R^(1.4) is independently unsubstituted tert-butyl. Inembodiments, R^(1.4) is independently unsubstituted pentyl. Inembodiments, R^(1.4) is independently unsubstituted hexyl. Inembodiments, R^(1.4) is independently unsubstituted heptyl. Inembodiments, R^(1.4) is independently unsubstituted octyl. Inembodiments, R^(1.4) is independently —F. In embodiments, R^(1.4) isindependently —Cl. In embodiments, R^(1.4) is independently —Br. Inembodiments, R^(1.4) is independently —I. In embodiments, R^(1.4) isindependently unsubstituted methoxy. In embodiments, R^(1.4) isindependently unsubstituted ethoxy. In embodiments, R^(1.4) isindependently —CF₃. In embodiments, R^(1.4) is independently —CCl₃. Inembodiments, R^(1.4) is an unsubstituted phenyl. In embodiments, R^(1.4)is an unsubstituted pyridyl. In embodiments, R^(1.4) is independentlyhalogen. In embodiments, R^(1.4) is independently —CONH₂. Inembodiments, R^(1.4) is independently —SO₃H. In embodiments, R^(1.4) isindependently —SO₄H. In embodiments, R^(1.4) is independently —SO₂NH₂.In embodiments, R^(1.4) is independently —NHNH₂. In embodiments, R^(1.4)is independently —ONH₂. In embodiments, R^(1.4) is independently—NHC(O)NHNH₂. In embodiments, R^(1.4) is independently —NHC(O)NH₂. Inembodiments, R^(1.4) is independently —NHSO₂H. In embodiments, R^(1.4)is independently —NHC(O)H. In embodiments, R^(1.4) is independently—NHC(O)OH. In embodiments, R^(1.4) is independently —NHOH. Inembodiments, X¹⁴ is independently —F. In embodiments, X¹⁴ isindependently —Cl. In embodiments, X¹⁴ is independently —Br. Inembodiments, X¹⁴ is independently —I.

R^(1.5) is independently hydrogen, halogen, —CX^(1.5) ₃, —CHX^(1.5) ₂,—CH₂X^(1.5), —CN, —SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B),—NHNR^(1A)R^(1B), —ONR^(1A)R^(1B), —NHC═(O)NHNR^(1A)R^(1B),—NHC(O)NR^(1A)R^(1B), —N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C),—C(O)—OR^(1C), —C(O)NR^(1A)R^(1B), —OR^(1D), —NR^(1A)SO₂R^(1D),—NR^(1A)C(O)R^(1C), —NR^(1A)C(O)OR^(1C), —NR^(1A)OR^(1C), —OCX^(1.5) ₃,—OCHX^(1.5) ₂, —OCH₂X^(1.5), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered,2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R^(1.5) isindependently hydrogen.

In embodiments, R^(1.5) is independently halogen, —CX^(1.5) ₃,—CHX^(1.5) ₂, —CH₂X^(1.5), —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCX^(1.5) ₃, —OCHX^(1.5) ₂, OCH₂X^(1.5),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted alkyl(e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R^(1.5) is independently halogen, —CX^(1.5) ₃,—CHX^(1.5) ₂, —CH₂X^(1.5), —OH, —CN, —SO₂CH₃, —NO₂, —N(CH₃)₂, —NH₂, —SH,—CO OH, —OCX^(1.5) ₃, —OCHX^(1.5) ₂, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃,—SCH₃, or —SCH₂CH₃.

In embodiments, R^(1.5) is substituted or unsubstituted C₁-C₆ alkyl. Inembodiments, R^(1.5) is substituted or unsubstituted 2 to 6 memberedheteroalkyl. In embodiments, R^(1.5) is substituted or unsubstitutedC₃-C₈ cycloalkyl. In embodiments, R^(1.5) is substituted orunsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R^(1.5)is substituted or unsubstituted phenyl. In embodiments, R^(1.5) issubstituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments,R^(1.5) is independently halogen. In embodiments, R^(1.5) isindependently —CX^(1.5) ₃. In embodiments, R^(1.5) is independently—CHX^(1.5) ₂. In embodiments, R^(1.5) is independently —CH₂X^(1.5). Inembodiments, R^(1.5) is independently —OH. In embodiments, R^(1.5) isindependently —SH. In embodiments, R^(1.5) is independently —COOH. Inembodiments, R^(1.5) is independently —OCX^(1.5) ₃. In embodiments,R^(1.5) is independently —OCHX^(1.5) ₂. In embodiments, R^(1.5) isindependently —OCH₂X^(1.5). In embodiments, R^(1.5) is independently—CH₃. In embodiments, R^(1.5) is independently —CH₂CH₃. In embodiments,R^(1.5) is independently —OCH₃. In embodiments, R^(1.5) is independently—OCH₂CH₃. In embodiments, R^(1.5) is independently —SCH₃. Inembodiments, R^(1.5) is independently —SCH₂CH₃. In embodiments, R^(1.5)is independently —CN. In embodiments, R^(1.5) is independently —SO₂CH₃.In embodiments, R^(1.5) is independently —NO₂. In embodiments, R^(1.5)is independently —N(CH₃)₂. In embodiments, R^(1.5) is independently—NH(CH₃). In embodiments, R^(1.5) is independently —NH(unsubstitutedphenyl). In embodiments, R^(1.5) is independently —NH(unsubstituted 5 to6 membered heteroaryl). In embodiments, R^(1.5) is independently —NH₂.In embodiments, R^(1.5) is independently unsubstituted methyl. Inembodiments, R^(1.5) is independently unsubstituted ethyl. Inembodiments, R^(1.5) is independently unsubstituted propyl. Inembodiments, R^(1.5) is independently unsubstituted n-propyl. Inembodiments, R^(1.5) is independently unsubstituted isopropyl. Inembodiments, R^(1.5) is independently unsubstituted butyl. Inembodiments, R^(1.5) is independently unsubstituted n-butyl. Inembodiments, R^(1.5) is independently unsubstituted isobutyl. Inembodiments, R^(1.5) is independently unsubstituted tert-butyl. Inembodiments, R^(1.5) is independently unsubstituted pentyl. Inembodiments, R^(1.5) is independently unsubstituted hexyl. Inembodiments, R^(1.5) is independently unsubstituted heptyl. Inembodiments, R^(1.5) is independently unsubstituted octyl. Inembodiments, R^(1.5) is independently —F. In embodiments, R^(1.5) isindependently —Cl. In embodiments, R^(1.5) is independently —Br. Inembodiments, R^(1.5) is independently —I. In embodiments, R^(1.5) isindependently unsubstituted methoxy. In embodiments, R^(1.5) isindependently unsubstituted ethoxy. In embodiments, R^(1.5) isindependently —CF₃. In embodiments, R^(1.5) is independently —CCl₃. Inembodiments, R^(1.5) is an unsubstituted phenyl. In embodiments, R^(1.5)is an unsubstituted pyridyl. In embodiments, R^(1.5) is independentlyhalogen. In embodiments, R^(1.5) is independently —CONH₂. Inembodiments, R^(1.5) is independently —SO₃H. In embodiments, R^(1.5) isindependently —SO₄H. In embodiments, R^(1.5) is independently —SO₂NH₂.In embodiments, R^(1.5) is independently —NHNH₂. In embodiments, R^(1.5)is independently —ONH₂. In embodiments, R^(1.5) is independently—NHC(O)NHNH₂. In embodiments, R^(1.5) is independently —NHC(O)NH₂. Inembodiments, R^(1.5) is independently —NHSO₂H. In embodiments, R^(1.5)is independently —NHC(O)H. In embodiments, R^(1.5) is independently—NHC(O)OH. In embodiments, R^(1.5) is independently —NHOH. Inembodiments, X^(1.5) is independently —F. In embodiments, X^(1.5) isindependently —Cl. In embodiments, X^(1.5) is independently —Br. Inembodiments, X^(1.5) is independently —I.

In embodiments, R² is independently hydrogen. In embodiments, R² is—C(O)R^(2A). In embodiments, R² is independently —C(O)OR^(2A). Inembodiments, R² is independently —C(O)NR^(2A)R^(2B). In embodiments, R²is independently —CX²³. In embodiments, R² is independently —CHX² ₂. Inembodiments, R² is independently —CH₂X². In embodiments, R² isindependently —OH. In embodiments, R² is independently —COOH. Inembodiments, R² is independently —OCX² ₃. In embodiments, R² isindependently —OCHX² ₂. In embodiments, R² is independently —CH₃. Inembodiments, R² is independently —CH₂CH₃. In embodiments, R² isindependently —OCH₃. In embodiments, R² is independently —OCH₂CH₃. Inembodiments, R² is independently unsubstituted methyl. In embodiments,R² is independently unsubstituted ethyl. In embodiments, R² isindependently unsubstituted propyl. In embodiments, R² is independentlyunsubstituted n-propyl. In embodiments, R² is independentlyunsubstituted isopropyl. In embodiments, R² is independentlyunsubstituted butyl. In embodiments, R² is independently unsubstitutedn-butyl. In embodiments, R² is independently unsubstituted isobutyl. Inembodiments, R² is independently unsubstituted tert-butyl. Inembodiments, R² is independently unsubstituted pentyl. In embodiments,R² is independently unsubstituted hexyl. In embodiments, R² isindependently unsubstituted heptyl. In embodiments, R² is independentlyunsubstituted octyl. In embodiments, R² is independently —CF₃. Inembodiments, R² is independently —CCl₃. In embodiments, X² isindependently —F. In embodiments, X² is independently —Cl. Inembodiments, X² is independently —Br. In embodiments, X² isindependently —I.

In embodiments, R² is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted alkyl. In embodiments, R² is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) alkyl. In embodiments, R² is unsubstitutedalkyl. In embodiments, R² is substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R² is substituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R² isunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).

In embodiments, R² is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroalkyl. In embodiments, R² is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) heteroalkyl. In embodiments, R² isunsubstituted heteroalkyl. In embodiments, R² is substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R² issubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R² is anunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered).

In embodiments, R² is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted cycloalkyl. In embodiments, R² is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) cycloalkyl. In embodiments, R² is anunsubstituted cycloalkyl. In embodiments, R² is substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R² is substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆). In embodiments, R² is unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆).

In embodiments, R² is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heterocycloalkyl. In embodiments, R² is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) heterocycloalkyl. In embodiments, R² is anunsubstituted heterocycloalkyl. In embodiments, R² is substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R² is substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R² an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

In embodiments, R² is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted aryl. In embodiments, R² is substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) aryl. In embodiments, R² is an unsubstituted aryl. Inembodiments, R² is substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl). In embodiments, R² is substituted aryl (e.g., C₆-C₁₀ orphenyl). In embodiments, R² is an unsubstituted aryl (e.g., C₆-C₁₀ orphenyl).

In embodiments, R² is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroaryl. In embodiments, R² is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) heteroaryl. In embodiments, R² is anunsubstituted heteroaryl. In embodiments, R² is substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). In embodiments, R² is substituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R² isan unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or5 to 6 membered).

In embodiments, each R^(2A) and R^(2B) is independently hydrogen, —CX₃,—CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered,2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, each R^(2A) and R^(2B)is independently hydrogen. In embodiments, each R^(2A) and R^(2B) isindependently —CX₃. In embodiments, each R^(2A) and R^(2B) isindependently —CN. In embodiments, each R^(2A) and R^(2B) isindependently —COOH. In embodiments, each R^(2A) and R^(2B) isindependently —CONH₂. In embodiments, each R^(2A) and R^(2B) isindependently —CHX₂. In embodiments, each R^(2A) and R^(2B) isindependently —CH₂X. In embodiments, each R^(2A) and R^(2B) isindependently —CH₃. In embodiments, each R^(2A) and R^(2B) isindependently —CH₂CH₃.

In embodiments, each R^(2A) and R^(2B) is independently hydrogen, —CX₃,—CN, —COOH, —CONH₂, —CHX₂, —CH₂X, unsubstituted alkyl (e.g., C₁-C₂₀,C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g.,2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R^(2A) and R^(2B) substituents bonded to the samenitrogen atom may optionally be joined to form a substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to5 membered, or 5 to 6 membered) or substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(2A) and R^(2B) substituents bonded to the same nitrogen atom mayoptionally be joined to independently form an unsubstitutedheterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, L¹ is a bond, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), or

In embodiments, L¹ is a bond, unsubstituted alkylene (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), or unsubstituted cycloalkylene (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). In embodiments, L¹ is a bond. In embodiments,L¹ is —CH₂—. In embodiments, L¹ is —C(CH₃)₂—. In embodiments, L¹ isunsubstituted cyclopropylene. In embodiments, L¹ is a bond. Inembodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is

In some embodiments, when Ring A is aryl, L¹ is a bond, substituted orunsubstituted alkylene, or substituted or unsubstituted cycloalkylene.

In embodiments, L¹ is a bond, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted alkylene (e.g., C₁-C₂₀, C₁-C₁₂,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkylene (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), or

In embodiments, L¹ is an unsubstituted methylene. In embodiments, L¹ isa bond. In embodiments, L¹ is

In embodiments, L¹ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted alkylene. In embodiments, L¹ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) alkylene. In embodiments, L¹ isunsubstituted alkylene. In embodiments, L¹ is substituted orunsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). Inembodiments, L¹ is substituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂). In embodiments, L¹ is unsubstituted alkylene (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂).

In embodiments, L¹ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted cycloalkylene. In embodiments, L¹ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) cycloalkylene. In embodiments, L¹ is anunsubstituted cycloalkylene. In embodiments, L¹ is substituted orunsubstituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, L¹ is substituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆). In embodiments, L¹ is unsubstituted cycloalkylene (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆).

In embodiments, L² is a bond, —O—, —C(O)—, —C(O)O—, —OC(O)—, —S—, —SO—,—S(O)₂—, —NH—, —NHC(O)—, —C(O)NH—, —SO₂NH—, —NHSO₂—, —OC(O)NH—,—NHC(O)O—, —NHC(O)NH—, —C(O)OCH₂—, —CH₂OC(O)—, —C(O)NHCH₂—, —CH₂NHC(O)—,—CH₂NHCH₂—, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), orsubstituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered,2 to 3 membered, or 4 to 5 membered). In embodiments, L² is a bond,—S(O)₂—, —C(O)OCH₂—, —CH₂OC(O)—, —C(O)NHCH₂—, —CH₂NHC(O)—, —CH₂NHCH₂—,or —CH₂—. In embodiments, L² is a bond. In embodiments, L² is —S(O)₂—.In embodiments, L² is —C(O)OCH₂—. In embodiments, L² is —C(O)NHCH₂—. Inembodiments, L² is —CH₂NHCH₂—. In embodiments, L² is —CH₂—. Inembodiments, L² is —CH₂CH₂—. In embodiments, L² is —C(CH₃)₂—. Inembodiments, L² is —O—. In embodiments, L² is —C(O)—. In embodiments, L²is —C(O)O—. In embodiments, L² is —OC(O)—. In embodiments, L² is —S—. Inembodiments, L² is —SO—. In embodiments, L² is —NH—. In embodiments, L²is —NHC(O)—. In embodiments, L² is —C(O)NH—. In embodiments, L² is—SO₂NH—. In embodiments, L² is —NHSO₂—. In embodiments, L² is —OC(O)NH—.In embodiments, L² is —NHC(O)O—. In embodiments, L² is —NHC(O)NH—. Inembodiments, L² is —CH₂OC(O)—. In embodiments, L² is —CH₂NHC(O)—. Inembodiments, L² is —CH₂CONH—. In embodiments, L² is

In embodiments, L² is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted alkylene. In embodiments, L² is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) alkylene. In embodiments, L² isunsubstituted alkylene. In embodiments, L² is substituted orunsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). Inembodiments, L² is substituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂). In embodiments, L² is unsubstituted alkylene (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂).

In embodiments, L² is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroalkylene. In embodiments, L² is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) heteroalkylene. In embodiments, L² isunsubstituted heteroalkylene. In embodiments, L² is substituted orunsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L²is substituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L²is an unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).

In embodiments, L³ is a bond, —S(O)₂—, —N(R³)—, —O—, —S—, —C(O)—,—C(O)N(R³)—, —N(R³)C(O)—, —N(R³)C(O)NH—, —NHC(O)N(R³)—, —C(O)O—,—OC(O)—, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted alkylene (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), substituted (e.g., substituted with a substituent group,a size-limited substituent group, or lower substituent group) orunsubstituted cycloalkylene (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted arylene (e.g., C₆-C₁₂, C₆-C₁₀, or phenylene), orsubstituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

In embodiments, L³ is a bond, —S(O)₂—, —NH—, —C(O)NH—, —NHC(O)—,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted C₁-C₆alkylene, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted 2 to 6 membered heteroalkylene, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted C₃-C₆ cycloalkylene,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted 3 to 6membered heterocycloalkylene, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted phenylene, or substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted 5 to 6 memberedheteroarylene.

In embodiments, L³ is a bond. In embodiments, L³ is —S(O)₂—. Inembodiments, L³ is —N(R³)—. In embodiments, L³ is —O—. In embodiments,L³ is —S—. In embodiments, L³ is —C(O)—. In embodiments, L³ is—C(O)N(R³)—. In embodiments, L³ is —N(R³)C(O)—. In embodiments, L³ is—N(R³)C(O)NH—. In embodiments, L³ is —NHC(O)N(R³)—. In embodiments, L³is —C(O)O—. In embodiments, L³ is —OC(O)—. In embodiments, L³ is —NH—.In embodiments, L³ is —C(O)NH—. In embodiments, L³ is —NHC(O)—. Inembodiments, L³ is —NHC(O)NH—. In embodiments, L³ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted methylene. In embodiments,L³ is unsubstituted methylene. In embodiments, L³ is

In embodiments, L³ is

In embodiments, L³ is

In embodiments, L³ is

In embodiments, L³ is

In embodiments, L³ is

In embodiments, L³ is a bond, substituted or unsubstituted methylene,substituted or unsubstituted ethylene, substituted or unsubstitutedpropylene, substituted or unsubstituted butylene, substituted orunsubstituted C₅ alkylene, substituted or unsubstituted C₆ alkylene,substituted or unsubstituted ethenylene, substituted or unsubstitutedpropenylene, substituted or unsubstituted butenylene, substituted orunsubstituted C₅ alkenylene, or substituted or unsubstituted C₆alkenylene. In embodiments, L³ is a bond, unsubstituted methylene,unsubstituted ethylene, unsubstituted propylene, unsubstituted butylene,unsubstituted C5 alkylene, unsubstituted C₆ alkylene, unsubstitutedethenylene, unsubstituted propenylene, unsubstituted butenylene,unsubstituted C5 alkenylene, or unsubstituted C₆ alkenylene. Inembodiments, L³ is a bond. In embodiments, L³ is a substituted orunsubstituted 2 membered heteroalkyl, substituted or unsubstituted 3membered heteroalkyl, substituted or unsubstituted 4 memberedheteroalkyl, substituted or unsubstituted 5 membered heteroalkyl,substituted or unsubstituted 6 membered heteroalkyl. In embodiments, L³is an unsubstituted 2 membered heteroalkyl, unsubstituted 3 memberedheteroalkyl, unsubstituted 4 membered heteroalkyl, unsubstituted 5membered heteroalkyl, or unsubstituted 6 membered heteroalkyl. Inembodiments, L³ is

In embodiments, L³ is

In embodiments, L³ is

In embodiments, L³ is

In embodiments, L³ is

In embodiments, L³ is

In embodiments, L³ is

In embodiments, L³ is

In embodiments, L³ is

In embodiments, L³ is

wherein R⁶ is as described herein.

In embodiments, L³ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted alkylene. In embodiments, L³ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) alkylene. In embodiments, L³ isunsubstituted alkylene. In embodiments, L³ is substituted orunsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). Inembodiments, L³ is substituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂). In embodiments, L³ is unsubstituted alkylene (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂).

In embodiments, L³ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroalkylene. In embodiments, L³ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) heteroalkylene. In embodiments, L³ isunsubstituted heteroalkylene. In embodiments, L³ is substituted orunsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L³is substituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L³is an unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).

In embodiments, L³ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted cycloalkylene. In embodiments, L³ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) cycloalkylene. In embodiments, L³ is anunsubstituted cycloalkylene. In embodiments, L³ is substituted orunsubstituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, L³ is substituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆). In embodiments, L³ is unsubstituted cycloalkylene (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆).

In embodiments, L³ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heterocycloalkylene. In embodiments, L³ is substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) heterocycloalkylene. In embodiments,L³ is an unsubstituted heterocycloalkylene. In embodiments, L³ issubstituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered,3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).In embodiments, L³ is substituted heterocycloalkylene (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered). In embodiments, L³ an unsubstituted heterocycloalkylene(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered).

In embodiments, L³ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted arylene. In embodiments, L³ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) arylene. In embodiments, L³ is anunsubstituted arylene. In embodiments, L³ is substituted orunsubstituted arylene (e.g., C₆-C₁₀ or phenylene). In embodiments, L³ issubstituted arylene (e.g., C₆-C₁₀ or phenylene). In embodiments, L³ isan unsubstituted arylene (e.g., C₆-C₁₀ or phenylene).

In embodiments, L³ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroarylene. In embodiments, L³ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) heteroarylene. In embodiments, L³ is anunsubstituted heteroarylene. In embodiments, L³ is substituted orunsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or5 to 6 membered). In embodiments, L³ is substituted heteroarylene (e.g.,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,L³ is an unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

In embodiments, L³ is a bond, —S(O)₂—, —N(R³)—, —O—, —S—, —C(O)—,—C(O)N(R³)—, —N(R³)C(O)—, —N(R³)C(O)NH—, —NHC(O)N(R³)—, —C(O)O—,—OC(O)—, R⁶-substituted or unsubstituted alkylene (e.g., C₁-C₂₀, C₁-C₁₂,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R⁶-substituted or unsubstitutedheteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R⁶-substituted or unsubstituted cycloalkylene (e.g., C₃-C₁₀,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R⁶-substituted or unsubstitutedheterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),R⁶-substituted or unsubstituted arylene (e.g., C₆-C₁₂, C₆-C₁₀, orphenylene), or R⁶-substituted or unsubstituted heteroarylene (e.g., 5 to12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R⁶ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CH₂Cl,—CH₂Br, —CH₂F, —CH₂I, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCBr₃, —OCF₃, —OCI₃, —OCH₂Cl, —OCH₂Br, —OCH₂F, —OCH₂I, —OCHCl₂,—OCHBr₂, —OCHF₂, —OCHI₂, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R⁶ is independently —OH, substituted orunsubstituted methyl, substituted or unsubstituted ethyl, substituted orunsubstituted propyl, substituted or unsubstituted butyl, substituted orunsubstituted C₅ alkyl, substituted or unsubstituted C₆ alkyl, —SO₂CH₃,substituted or unsubstituted 2 membered heteroalkyl, substituted orunsubstituted 3 membered heteroalkyl, substituted or unsubstituted 4membered heteroalkyl, substituted or unsubstituted 5 memberedheteroalkyl, or substituted or unsubstituted 6 membered heteroalkyl.

In embodiments, R⁶ is independently —OH, unsubstituted methyl,unsubstituted ethyl, unsubstituted propyl, unsubstituted butyl,unsubstituted C₅ alkyl, unsubstituted C₆ alkyl, —SO₂CH₃, unsubstituted 2membered heteroalkyl, unsubstituted 3 membered heteroalkyl,unsubstituted 4 membered heteroalkyl, unsubstituted 5 memberedheteroalkyl, or unsubstituted 6 membered heteroalkyl.

In embodiments, R⁶ is independently oxo. In embodiments, R⁶ isindependently halogen. In embodiments, R⁶ is independently —CCl₃. Inembodiments, R⁶ is independently —CBr₃. In embodiments, R⁶ isindependently —CF₃. In embodiments, R⁶ is independently —CI₃. Inembodiments, R⁶ is independently —CH₂Cl. In embodiments, R⁶ isindependently —CH₂Br. In embodiments, R⁶ is independently —CH₂F. Inembodiments, R⁶ is independently —CH₂I. In embodiments, R⁶ isindependently —CHCl₂. In embodiments, R⁶ is independently —CHBr₂. Inembodiments, R⁶ is independently —CHF₂. In embodiments, R⁶ isindependently —CHI₂. In embodiments, R⁶ is independently —CN. Inembodiments, R⁶ is independently —OH. In embodiments, R⁶ isindependently —NH₂. In embodiments, R⁶ is independently —COOH. Inembodiments, R⁶ is independently —CONH₂. In embodiments, R⁶ isindependently —NO₂. In embodiments, R⁶ is independently —SH. Inembodiments, R⁶ is independently —SO₃H. In embodiments, R⁶ isindependently —SO₄H. In embodiments, R⁶ is independently —SO₂NH₂. Inembodiments, R⁶ is independently —NHNH₂. In embodiments, R⁶ isindependently —ONH₂. In embodiments, R⁶ is independently —NHC(O)NHNH₂.In embodiments, R⁶ is independently —NHC(O)NH₂. In embodiments, R⁶ isindependently —NHSO₂H. In embodiments, R⁶ is independently —NHC(O)H. Inembodiments, R⁶ is independently —NHC(O)OH. In embodiments, R⁶ isindependently —NHOH. In embodiments, R⁶ is independently —OCCl₃. Inembodiments, R⁶ is independently —OCBr₃. In embodiments, R⁶ isindependently —OCF₃. In embodiments, R⁶ is independently —OCI₃. Inembodiments, R⁶ is independently —OCH₂Cl. In embodiments, R⁶ isindependently —OCH₂Br. In embodiments, R⁶ is independently —OCH₂F. Inembodiments, R⁶ is independently —OCH₂I. In embodiments, R⁶ isindependently —OCHCl₂. In embodiments, R⁶ is independently —OCHBr₂. Inembodiments, R⁶ is independently —OCHF₂. In embodiments, R⁶ isindependently —OCHI₂.

In embodiments, R⁶ is independently —OH. In embodiments, R⁶ isindependently unsubstituted methyl. In embodiments, R⁶ is independentlyunsubstituted ethyl. In embodiments, R⁶ is independently unsubstitutedpropyl. In embodiments, R⁶ is independently unsubstituted butyl. Inembodiments, R⁶ is independently unsubstituted C₅ alkyl. In embodiments,R⁶ is independently unsubstituted C₆ alkyl. In embodiments, R⁶ isindependently —SO₂CH₃. In embodiments, R⁶ is independently unsubstituted2 membered heteroalkyl. In embodiments, R⁶ is independentlyunsubstituted 3 membered heteroalkyl. In embodiments, R⁶ isindependently unsubstituted 4 membered heteroalkyl. In embodiments, R⁶is independently unsubstituted 5 membered heteroalkyl. In embodiments,R⁶ is independently unsubstituted 6 membered heteroalkyl.

In embodiments, R³ is independently hydrogen, —CX³ ₃, —CHX³ ₂, —CH₂X³,—C(O)R^(3A), —C(O)OR^(3A), —C(O)NR^(3A)R^(3B), substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted alkyl (e.g., C₁-C₂₀,C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered,2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R³ is independentlyhydrogen. In embodiments, R³ is independently —CX³³. In embodiments, R³is independently —CHX³². In embodiments, R³ is independently —CH₂X³. Inembodiments, R³ is independently —C(O)R^(3A)In embodiments, R³ isindependently —C(O)OR^(3A). In embodiments, R³ is independently—C(O)NR^(3A)R^(3B). In embodiments, R³ is independently —CH₃. Inembodiments, R³ is independently —CH₂CH₃. In embodiments, R³ isindependently —C(O)H. In embodiments, R³ is independently —C(O)OH. Inembodiments, R³ is independently —C(O)NH₂. In embodiments, X³ isindependently —F. In embodiments, X³ is independently —Cl. Inembodiments, X³ is independently —Br. In embodiments, X³ isindependently —I.

In embodiments, R³ is independently hydrogen, —CX³ ₃, —CHX³ ₂, —CH₂X³,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted alkyl(e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R³ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted alkyl. In embodiments, R³ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) alkyl. In embodiments, R³ is unsubstitutedalkyl. In embodiments, R³ is substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R³ is substituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R³ isunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).

In embodiments, R³ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroalkyl. In embodiments, R³ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) heteroalkyl. In embodiments, R³ isunsubstituted heteroalkyl. In embodiments, R³ is substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R³ issubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R³ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered).

In embodiments, R³ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted cycloalkyl. In embodiments, R³ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) cycloalkyl. In embodiments, R³ is anunsubstituted cycloalkyl. In embodiments, R³ is substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R³ is substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆). In embodiments, R³ is unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆).

In embodiments, R³ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heterocycloalkyl. In embodiments, R³ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) heterocycloalkyl. In embodiments, R³ is anunsubstituted heterocycloalkyl. In embodiments, R³ is substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R³ is substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R³ an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

In embodiments, R³ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted aryl. In embodiments, R³ is substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) aryl. In embodiments, R³ is an unsubstituted aryl. Inembodiments, R³ is substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl). In embodiments, R³ is substituted aryl (e.g., C₆-C₁₀ orphenyl). In embodiments, R³ is an unsubstituted aryl (e.g., C₆-C₁₀ orphenyl).

In embodiments, R³ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroaryl. In embodiments, R³ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) heteroaryl. In embodiments, R³ is anunsubstituted heteroaryl. In embodiments, R³ is substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). In embodiments, R³ is substituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R³ isan unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or5 to 6 membered).

In embodiments, each R^(3A) and R^(3B) is independently hydrogen, —CX₃,—CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered,2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, each R^(3A) and R^(3B)is independently hydrogen. In embodiments, each R^(3A) and R^(3B) isindependently —CX₃. In embodiments, each each R^(3A) and R^(3B) isindependently —CN. In embodiments, each R^(3A) and R^(3B) isindependently —COOH. In embodiments, each R^(3A) and R^(3B) isindependently —CONH₂. In embodiments, each R^(3A) and R^(3B) isindependently —CHX₂. In embodiments, each R^(3A) and R^(3B) isindependently —CH₂X. In embodiments, each R^(3A) and R^(3B) isindependently —CH₃. In embodiments, each R^(3A) and R^(3B) isindependently —CH₂CH₃.

In embodiments, each R^(3A) and R^(3B) is independently hydrogen, —CX₃,—CN, —COOH, —CONH₂, —CHX₂, —CH₂X, unsubstituted alkyl (e.g., C₁-C₂₀,C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g.,2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R^(3A) and R^(3B) substituents bonded to the samenitrogen atom may optionally be joined to form a substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to5 membered, or 5 to 6 membered) or substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(3A) and R^(3B) substituents bonded to the same nitrogen atom mayoptionally be joined to independently form an unsubstitutedheterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, L⁴ is a bond, —S(O)₂—, —N(R⁴)—, —O—, —S—, —C(O)—,—C(O)N(R⁴)—, —N(R⁴)C(O)—, —N(R⁴)C(O)NH—, —NHC(O)N(R⁴)—, —C(O)O—,—OC(O)—, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted alkylene (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), substituted (e.g., substituted with a substituent group,a size-limited substituent group, or lower substituent group) orunsubstituted cycloalkylene (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heterocycloalkylene (e.g., 3 to 10 membered, 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted arylene (e.g., C₆-C₁₂, C₆-C₁₀, or phenylene), orsubstituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

In embodiments, L⁴ is a bond, —S(O)₂—, —NH—, —C(O)NH—, —NHC(O)—,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted C₁-C₆alkylene, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted 2 to 6 membered heteroalkylene, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted C₃-C₆ cycloalkylene,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted 3 to 6membered heterocycloalkylene, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted phenylene, or substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted 5 to 6 memberedheteroarylene.

In embodiments, L⁴ is a bond. In embodiments, L⁴ is —S(O)₂—. Inembodiments, L⁴ is —N(R⁴)—. In embodiments, L⁴ is —O—. In embodiments,L⁴ is —S—. In embodiments, L⁴ is —C(O)—. In embodiments, L⁴ is—C(O)N(R⁴)—. In embodiments, L⁴ is —N(R⁴)C(O)—. In embodiments, L⁴ is—N(R⁴)C(O)NH—. In embodiments, L⁴ is —NHC(O)N(R⁴)—. In embodiments, L⁴is —C(O)O—. In embodiments, L⁴ is —OC(O)—. In embodiments, L⁴ is —NH—.In embodiments, L⁴ is —C(O)NH—. In embodiments, L⁴ is —NHC(O)—. Inembodiments, L⁴ is —NHC(O)NH—. In embodiments, L⁴ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted methylene. In embodiments,L⁴ is unsubstituted methylene. In embodiments, L⁴ is

In embodiments, L⁴ is

In embodiments, L⁴ is

In embodiments, L⁴ is

In embodiments, L⁴ is

In embodiments, L⁴ is

In embodiments, L⁴ is a bond, substituted or unsubstituted methylene,substituted or unsubstituted ethylene, substituted or unsubstitutedpropylene, substituted or unsubstituted butylene, substituted orunsubstituted C₅ alkylene, substituted or unsubstituted C₆ alkylene,substituted or unsubstituted ethenylene, substituted or unsubstitutedpropenylene, substituted or unsubstituted butenylene, substituted orunsubstituted C₅ alkenylene, or substituted or unsubstituted C₆alkenylene. In embodiments, L⁴ is a bond, unsubstituted methylene,unsubstituted ethylene, unsubstituted propylene, unsubstituted butylene,unsubstituted C5 alkylene, unsubstituted C₆ alkylene, unsubstitutedethenylene, unsubstituted propenylene, unsubstituted butenylene,unsubstituted C5 alkenylene, or unsubstituted C₆ alkenylene. Inembodiments, L⁴ is a bond. In embodiments, L⁴ is a substituted orunsubstituted 2 membered heteroalkyl, substituted or unsubstituted 3membered heteroalkyl, substituted or unsubstituted 4 memberedheteroalkyl, substituted or unsubstituted 5 membered heteroalkyl,substituted or unsubstituted 6 membered heteroalkyl. In embodiments, L⁴is an unsubstituted 2 membered heteroalkyl, unsubstituted 3 memberedheteroalkyl, unsubstituted 4 membered heteroalkyl, unsubstituted 5membered heteroalkyl, or unsubstituted 6 membered heteroalkyl. Inembodiments, L⁴ is

In embodiments, L⁴ is

In embodiments, L⁴ is

In embodiments, L⁴ is

In embodiments, L⁴ is

In embodiments, L⁴ is

In embodiments, L⁴ is

In embodiments, L⁴ is

In embodiments, L⁴ is

In embodiments, L³ is

wherein R⁷ is as described herein.

In embodiments, L⁴ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted alkylene. In embodiments, L⁴ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) alkylene. In embodiments, L⁴ isunsubstituted alkylene. In embodiments, L⁴ is substituted orunsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). Inembodiments, L⁴ is substituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂). In embodiments, L⁴ is unsubstituted alkylene (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂).

In embodiments, L⁴ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroalkylene. In embodiments, L⁴ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) heteroalkylene. In embodiments, L⁴ isunsubstituted heteroalkylene. In embodiments, L⁴ is substituted orunsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L⁴is substituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L⁴is an unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).

In embodiments, L⁴ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted cycloalkylene. In embodiments, L⁴ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) cycloalkylene. In embodiments, L⁴ is anunsubstituted cycloalkylene. In embodiments, L⁴ is substituted orunsubstituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, L⁴ is substituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆). In embodiments, L⁴ is unsubstituted cycloalkylene (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆).

In embodiments, L⁴ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heterocycloalkylene. In embodiments, L⁴ is substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) heterocycloalkylene. In embodiments,L⁴ is an unsubstituted heterocycloalkylene. In embodiments, L⁴ issubstituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered,3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).In embodiments, L⁴ is substituted heterocycloalkylene (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered). In embodiments, L⁴ an unsubstituted heterocycloalkylene(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered).

In embodiments, L⁴ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted arylene. In embodiments, L⁴ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) arylene. In embodiments, L⁴ is anunsubstituted arylene. In embodiments, L⁴ is substituted orunsubstituted arylene (e.g., C₆-C₁₀ or phenylene). In embodiments, L⁴ issubstituted arylene (e.g., C₆-C₁₀ or phenylene). In embodiments, L⁴ isan unsubstituted arylene (e.g., C₆-C₁₀ or phenylene).

In embodiments, L⁴ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroarylene. In embodiments, L⁴ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) heteroarylene. In embodiments, L⁴ is anunsubstituted heteroarylene. In embodiments, L⁴ is substituted orunsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or5 to 6 membered). In embodiments, L⁴ is substituted heteroarylene (e.g.,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,L⁴ is an unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

In embodiments, L⁴ is a bond, —S(O)₂—, —N(R⁴)—, —O—, —S—, —C(O)—,—C(O)N(R⁴)—, —N(R⁴)C(O)—, —N(R⁴)C(O)NH—, —NHC(O)N(R⁴)—, —C(O)O—,—OC(O)—, R⁷-substituted or unsubstituted alkylene (e.g., C₁-C₂₀, C₁-C₁₂,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R⁷-substituted or unsubstitutedheteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R⁷-substituted or unsubstituted cycloalkylene (e.g., C₃-C₁₀,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R⁷-substituted or unsubstitutedheterocycloalkylene (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),R⁷-substituted or unsubstituted arylene (e.g., C₆-C₁₂, C₆-C₁₀, orphenylene), or R-substituted or unsubstituted heteroarylene (e.g., 5 to12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R⁷ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CH₂Cl,—CH₂Br, —CH₂F, —CH₂I, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCBr₃, —OCF₃, —OCI₃, —OCH₂Cl, —OCH₂Br, —OCH₂F, —OCH₂I, —OCHCl₂,—OCHBr₂, —OCHF₂, —OCHI₂, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R⁷ is independently —OH, substituted orunsubstituted methyl, substituted or unsubstituted ethyl, substituted orunsubstituted propyl, substituted or unsubstituted butyl, substituted orunsubstituted C₅ alkyl, substituted or unsubstituted C₆ alkyl, —SO₂CH₃,substituted or unsubstituted 2 membered heteroalkyl, substituted orunsubstituted 3 membered heteroalkyl, substituted or unsubstituted 4membered heteroalkyl, substituted or unsubstituted 5 memberedheteroalkyl, or substituted or unsubstituted 6 membered heteroalkyl.

In embodiments, R⁷ is independently —OH, unsubstituted methyl,unsubstituted ethyl, unsubstituted propyl, unsubstituted butyl,unsubstituted C₅ alkyl, unsubstituted C₆ alkyl, —SO₂CH₃, unsubstituted 2membered heteroalkyl, unsubstituted 3 membered heteroalkyl,unsubstituted 4 membered heteroalkyl, unsubstituted 5 memberedheteroalkyl, or unsubstituted 6 membered heteroalkyl.

In embodiments, R⁷ is independently oxo. In embodiments, R⁷ isindependently halogen. In embodiments, R⁷ is independently —CCl₃. Inembodiments, R⁷ is independently —CBr₃. In embodiments, R⁷ isindependently —CF₃. In embodiments, R⁷ is independently —CI₃. Inembodiments, R⁷ is independently —CH₂Cl. In embodiments, R⁷ isindependently —CH₂Br. In embodiments, R⁷ is independently —CH₂F. Inembodiments, R⁷ is independently —CH₂I. In embodiments, R⁷ isindependently —CHCl₂. In embodiments, R⁷ is independently —CHBr₂. Inembodiments, R⁷ is independently —CHF₂. In embodiments, R⁷ isindependently —CHI₂. In embodiments, R⁷ is independently —CN. Inembodiments, R⁷ is independently —OH. In embodiments, R⁷ isindependently —NH₂. In embodiments, R⁷ is independently —COOH. Inembodiments, R⁷ is independently —CONH₂. In embodiments, R⁷ isindependently —NO₂. In embodiments, R⁷ is independently —SH. Inembodiments, R⁷ is independently —SO₃H. In embodiments, R⁷ isindependently —SO₄H. In embodiments, R⁷ is independently —SO₂NH₂. Inembodiments, R⁷ is independently —NHNH₂. In embodiments, R⁷ isindependently —ONH₂. In embodiments, R⁷ is independently —NHC(O)NHNH₂.In embodiments, R⁷ is independently —NHC(O)NH₂. In embodiments, R⁷ isindependently —NHSO₂H. In embodiments, R⁷ is independently —NHC(O)H. Inembodiments, R⁷ is independently —NHC(O)OH. In embodiments, R⁷ isindependently —NHOH. In embodiments, R⁷ is independently —OCCl₃. Inembodiments, R⁷ is independently —OCBr₃. In embodiments, R⁷ isindependently —OCF₃. In embodiments, R⁷ is independently —OCI₃. Inembodiments, R⁷ is independently —OCH₂Cl. In embodiments, R⁷ isindependently —OCH₂Br. In embodiments, R⁷ is independently —OCH₂F. Inembodiments, R⁷ is independently —OCH₂I. In embodiments, R⁷ isindependently —OCHCl₂. In embodiments, R⁷ is independently —OCHBr₂. Inembodiments, R⁷ is independently —OCHF₂. In embodiments, R⁷ isindependently —OCHI₂.

In embodiments, R⁷ is independently —OH. In embodiments, R⁷ isindependently unsubstituted methyl. In embodiments, R⁷ is independentlyunsubstituted ethyl. In embodiments, R⁷ is independently unsubstitutedpropyl. In embodiments, R⁷ is independently unsubstituted butyl. Inembodiments, R⁷ is independently unsubstituted C₅ alkyl. In embodiments,R⁷ is independently unsubstituted C₆ alkyl. In embodiments, R⁷ isindependently —SO₂CH₃. In embodiments, R⁷ is independently unsubstituted2 membered heteroalkyl. In embodiments, R⁷ is independentlyunsubstituted 3 membered heteroalkyl. In embodiments, R⁷ isindependently unsubstituted 4 membered heteroalkyl. In embodiments, R⁷is independently unsubstituted 5 membered heteroalkyl. In embodiments,R⁷ is independently unsubstituted 6 membered heteroalkyl.

In embodiments, R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴,—C(O)R^(4A), —C(O)OR^(4A), —C(O)NR^(4A)R^(4B), substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted alkyl (e.g., C₁-C₂₀,C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered,2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, R⁴ is independentlyhydrogen. In embodiments, R⁴ is independently —CX⁴³. In embodiments, R⁴is independently —CHX⁴². In embodiments, R⁴ is independently —CH₂X⁴. Inembodiments, R⁴ is independently —C(O)R^(4A)In embodiments, R⁴ isindependently —C(O)OR^(4A). In embodiments, R⁴ is independently—C(O)NR^(4A)R^(4B). In embodiments, R⁴ is independently —CH₃. Inembodiments, R⁴ is independently —CH₂CH₃. In embodiments, R⁴ isindependently —C(O)H. In embodiments, R⁴ is independently —C(O)OH. Inembodiments, R⁴ is independently —C(O)NH₂. In embodiments, X⁴ isindependently —F. In embodiments, X⁴ is independently —Cl. Inembodiments, X⁴ is independently —Br. In embodiments, X⁴ isindependently —I.

In embodiments, R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted alkyl(e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heteroalkyl (e.g., 2to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R⁴ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted alkyl. In embodiments, R⁴ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) alkyl. In embodiments, R⁴ is unsubstitutedalkyl. In embodiments, R⁴ is substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁴ is substituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁴ isunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).

In embodiments, R⁴ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroalkyl. In embodiments, R⁴ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) heteroalkyl. In embodiments, R⁴ isunsubstituted heteroalkyl. In embodiments, R⁴ is substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R⁴ issubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R⁴ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered).

In embodiments, R⁴ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted cycloalkyl. In embodiments, R⁴ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) cycloalkyl. In embodiments, R⁴ is anunsubstituted cycloalkyl. In embodiments, R⁴ is substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R⁴ is substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆). In embodiments, R⁴ is unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆).

In embodiments, R⁴ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heterocycloalkyl. In embodiments, R⁴ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) heterocycloalkyl. In embodiments, R⁴ is anunsubstituted heterocycloalkyl. In embodiments, R⁴ is substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R⁴ is substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R⁴ an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

In embodiments, R⁴ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted aryl. In embodiments, R⁴ is substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) aryl. In embodiments, R⁴ is an unsubstituted aryl. Inembodiments, R⁴ is substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl). In embodiments, R⁴ is substituted aryl (e.g., C₆-C₁₀ orphenyl). In embodiments, R⁴ is an unsubstituted aryl (e.g., C₆-C₁₀ orphenyl).

In embodiments, R⁴ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroaryl. In embodiments, R⁴ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) heteroaryl. In embodiments, R⁴ is anunsubstituted heteroaryl. In embodiments, R⁴ is substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). In embodiments, R⁴ is substituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R⁴ isan unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or5 to 6 membered).

In embodiments, each R^(4A) and R^(4B) is independently hydrogen, —CX₃,—CN, —COOH, —CONH₂, —CHX₂, —CH₂X, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered,2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). In embodiments, each R^(4A) and R^(4B)is independently hydrogen. In embodiments, each R^(4A) and R^(4B) isindependently —CX₃. In embodiments, each each R^(4A) and R^(4B) isindependently —CN. In embodiments, each R^(4A) and R^(4B) isindependently —COOH. In embodiments, each R^(4A) and R^(4B) isindependently —CONH₂. In embodiments, each R^(4A) and R^(4B) isindependently —CHX₂. In embodiments, each R^(4A) and R^(4B) isindependently —CH₂X. In embodiments, each R^(4A) and R^(4B) isindependently —CH₃. In embodiments, each R^(4A) and R^(4B) isindependently —CH₂CH₃.

In embodiments, each R^(4A) and R^(4B) is independently hydrogen, —CX₃,—CN, —COOH, —CONH₂, —CHX₂, —CH₂X, unsubstituted alkyl (e.g., C₁-C₂₀,C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g.,2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered,or 5 to 6 membered).

In embodiments, R^(4A) and R^(4B) substituents bonded to the samenitrogen atom may optionally be joined to form a substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heterocycloalkyl (e.g., 3to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to5 membered, or 5 to 6 membered) or substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments,R^(4A) and R^(4B) substituents bonded to the same nitrogen atom mayoptionally be joined to independently form an unsubstitutedheterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiment, L⁴-R⁵ has the formula:

In embodiments, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L¹-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiment, L³-L⁴-R⁵ has the formula:

In embodiments, R⁵ is independently hydrogen, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted alkyl (e.g., C₁-C₂₀,C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered,2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered), or E.

In embodiments, R⁵ is independently hydrogen, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted alkyl (e.g., C₁-C₂₀,C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroalkyl (e.g., 2 to 20 membered,2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R⁵ is independently substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted C₁-C₆ alkyl, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted 2 to 6 memberedheteroalkyl, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted C₃-C₆ cycloalkyl, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted 3 to 6 membered heterocycloalkyl,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted phenyl,or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted 5 to 6 membered heteroaryl.

In embodiments, R⁵ is independently substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted 3 to 6 membered heterocycloalkyl orsubstituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted 5 to 6membered heteroaryl.

In embodiments, R⁵ is independently 3 to 6 membered heterocycloalkyl or5 to 6 membered heteroaryl; optionally substituted with one or moreindependent substituent groups, size-limited substituent groups, orlower substituent groups.

In embodiments, R⁵ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted alkyl. In embodiments, R⁵ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) alkyl. In embodiments, R⁵ is unsubstitutedalkyl. In embodiments, R⁵ is substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁵ is substituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁵ isunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).

In embodiments, R⁵ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroalkyl. In embodiments, R⁵ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) heteroalkyl. In embodiments, R⁵ isunsubstituted heteroalkyl. In embodiments, R⁵ is substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R⁵ issubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, R⁵ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered).

In embodiments, R⁵ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted cycloalkyl. In embodiments, R⁵ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) cycloalkyl. In embodiments, R⁵ is anunsubstituted cycloalkyl. In embodiments, R⁵ is substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). Inembodiments, R⁵ is substituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆). In embodiments, R⁵ is unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆).

In embodiments, R⁵ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heterocycloalkyl. In embodiments, R⁵ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) heterocycloalkyl. In embodiments, R⁵ is anunsubstituted heterocycloalkyl. In embodiments, R⁵ is substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R⁵ is substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). Inembodiments, R⁵ an unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered).

In embodiments, R⁵ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted aryl. In embodiments, R⁵ is substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) aryl. In embodiments, R⁵ is an unsubstituted aryl. Inembodiments, R⁵ is substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl). In embodiments, R⁵ is substituted aryl (e.g., C₆-C₁₀ orphenyl). In embodiments, R⁵ is an unsubstituted aryl (e.g., C₆-C₁₀ orphenyl).

In embodiments, R⁵ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroaryl. In embodiments, R⁵ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) heteroaryl. In embodiments, R⁵ is anunsubstituted heteroaryl. In embodiments, R⁵ is substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). In embodiments, R⁵ is substituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R⁵ isan unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or5 to 6 membered).

In embodiments, R⁵ is independently R¹³-substituted or unsubstitutedalkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R¹³-substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R¹³-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R¹³-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R¹³-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR¹³-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁵ is R¹³-substituted or unsubstituted alkyl (e.g.,C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl). In embodiments, R⁵ isR¹³-substituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl).In embodiments, R⁵ is an unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl).

In embodiments, R⁵ is R¹³-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to4 membered heteroalkyl). In embodiments, R⁵ is R¹³-substitutedheteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R⁵ is anunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl).

In embodiments, R⁵ is R¹³-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). Inembodiments, R⁵ is R¹³-substituted cycloalkyl (e.g., C₃-C₈ cycloalkyl,C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl). In embodiments, R⁵ is anunsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, orC₅-C₆ cycloalkyl).

In embodiments, R⁵ is R¹³-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl). In embodiments,R⁵ is R¹³-substituted heterocycloalkyl (e.g., 3 to 8 memberedheterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl). In embodiments, R⁵ is an unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl).

In embodiments, R⁵ is R¹³-substituted or unsubstituted aryl (e.g.,C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁵ is R¹³-substitutedaryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl). In embodiments, R⁵ is anunsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl).

In embodiments, R⁵ is R¹³-substituted or unsubstituted heteroaryl (e.g.,5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R⁵ is R¹³-substituted heteroaryl(e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to6 membered heteroaryl). In embodiments, R⁵ is an unsubstitutedheteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

R¹³ is independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃,CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —OR¹⁴, —S(O)₂R¹⁴, R¹⁴-substituted orunsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R¹⁴-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R¹⁴-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl), R¹⁴-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl,3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R¹⁴-substituted or unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, orphenyl), or R¹⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R¹³ is independently oxo, halogen (e.g.,—F), unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl,unsubstituted butyl, unsubstituted C₅ alkyl, or unsubstituted C₆ alkyl.In embodiments, R¹³ is independently oxo. In embodiments, R¹³ isindependently halogen (e.g., —F). In embodiments, R¹³ is independentlyunsubstituted methyl. In embodiments, R¹³ is independently unsubstitutedethyl. In embodiments, R¹³ is independently unsubstituted propyl. Inembodiments, R¹³ is independently unsubstituted butyl. In embodiments,R¹³ is independently unsubstituted C₅ alkyl. In embodiments, R¹³ isindependently unsubstituted C₆ alkyl.

R¹⁴ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, R¹⁵-substituted or unsubstituted alkyl(e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R¹⁵-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), R¹⁵-substitutedor unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl,or C₅-C₆ cycloalkyl), R¹⁵-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R¹⁵-substitutedor unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), orR¹⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

R¹⁵ is independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃,—CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCBr₃, —OCF₃, —OCI₃, —OCH₂Cl, —OCH₂Br, —OCH₂F, —OCH₂I, —OCHCl₂,—OCHBr₂, —OCHF₂, —OCHI₂, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g.,3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀ aryl,C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl).

In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R⁵ is

wherein z13 is an integer from 0 to 12. In embodiments, z13 is 0. Inembodiments, z13 is 1. In embodiments, z13 is 2.

In embodiments, R⁵ is

In embodiments, R⁵ is

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In embodiments, R⁵ is

wherein R¹³ and z13 are as described herein, including embodiments.

In embodiments, R⁵ is

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In embodiments, R⁵ is substituted or unsubstituted oziranyl, substitutedor unsubstituted oxetanyl, substituted or unsubstituted furanyl,substituted or unsubstituted pyrazinyl, substituted or unsubstitutedpyrimidinyl, substituted or unsubstituted triazinyl, substituted orunsubstituted pyridazinyl, substituted or unsubstituted pyridinyl,substituted or unsubstituted phenyl, —SO₂F, —COH,

In embodiments, R⁵ is substituted oziranyl, substituted oxetanyl,substituted furanyl, substituted pyrazinyl, substituted pyrimidinyl,substituted triazinyl, substituted pyridazinyl, substituted pyridinyl,substituted phenyl, —SO₂F, —COH,

In embodiments, R⁵ is unsubstituted oziranyl, unsubstituted oxetanyl,unsubstituted furanyl, unsubstituted pyrazinyl, unsubstitutedpyrimidinyl, unsubstituted triazinyl, unsubstituted pyridazinyl,unsubstituted pyridinyl, unsubstituted phenyl, —SO₂F, —COH,

In embodiments, R⁵ is E. In embodiments, E is a covalent histidinebinding moiety.

In embodiments, E is

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In embodiments, E is

R¹⁶ is independently hydrogen, halogen, CX¹⁶ ₃, —CHX¹⁶ ₂, —CH₂X¹⁶, —CN,—SO₂Cl, —SO_(n16)R^(16D), —SO_(v16)NR^(16A)R^(16B), —NHNR^(16A)R^(16B),—ONR^(16A)R^(16B), —NHC═(O)NHNR^(16A)R^(16B), —NHC(O)NR^(16A)R^(16B),—N(O)_(m16), —NR^(16A)R^(16B), —C(O)R^(16C), —C(O)—OR^(16C),—C(O)NR^(16A)R^(16B), —OR^(16D), —NR^(16A)SO₂R^(16D),—NR^(16A)C(O)R^(16C), —NR^(16A)C(O)OR^(16C), —NR^(16A)OR^(16C), —OCX¹⁶₃, —OCHX¹⁶ ₂, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), substituted (e.g., substituted with a substituent group,a size-limited substituent group, or lower substituent group) orunsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R¹⁷ is independently hydrogen, halogen, CX¹⁷ ₃, —CHX¹⁷ ₂, —CH₂X¹⁷, —CN,—SO₂Cl, —SO_(n17)R^(17D), —SO_(v17)NR^(17A)R^(17B), —NHNR^(17A)R^(17B),—ONR^(17A)R^(17B), —NHC═(O)NHNR^(17A)R^(17B), —NHC(O)NR¹⁷AR^(17B),—N(O)_(m17), —NR^(17A)R¹⁷B, C(O)R^(17C), —C(O)—OR^(17C),C(O)NR^(17A)R^(17B), —OR^(17D), —NR^(17A)SO₂R^(17D),—NR^(17A)C(O)R^(17C), —NR^(17A)C(O)OR^(17C), —NR^(17A)OR^(17C), —OCX¹⁷₃, —OCHX¹⁷ ₂, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), substituted (e.g., substituted with a substituent group,a size-limited substituent group, or lower substituent group) orunsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R¹⁸ is independently hydrogen, halogen, CX¹⁸ ₃, —CHX¹⁸ ₂, —CH₂X¹⁸, —CN,—SO₂Cl, —SO_(n18)R^(18D), —SO_(v18)NR^(18A)R^(18B), —NHNR^(18A)R^(18B),—ONR^(18A)R^(18B), —NHC═(O)NHNR^(18A)R^(18B), —NHC(O)NR^(18A)R^(18B),—N(O)_(m18), —NR^(18A)R^(18B), —C(O)R^(18C), —C(O)—OR^(18C),—C(O)NR^(18A)R^(18B), —OR^(18D), —NR^(18A)SO₂R^(18D),—NR^(18A)C(O)R^(18C), —NR^(18A)C(O)OR^(8C), —NR^(18A)OR^(18C), —OCX¹⁸ ₃,—OCHX¹⁸ ₂, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), substituted (e.g., substituted with a substituent group,a size-limited substituent group, or lower substituent group) orunsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R¹⁹ is independently hydrogen, halogen, CX¹⁹ ₃, —CHX¹⁹ ₂, —CH₂X¹⁹, —CN,—SO₂Cl, —SO_(n19)R^(19D), —SO_(v19)NR^(19A)R^(19B), —NHNR^(19A)R^(19B),—ONR^(19A)R^(19B), —NHC═(O)NHNR^(19A)R^(19B), —NHC(O)NR^(19A)R^(19B),—N(O)_(m19), —NR^(19A)R^(19B), —C(O)R^(19C), —C(O)—OR^(19C),—C(O)NR^(19A)R^(19B), —OR^(19D), NR^(19A)SO₂R^(19D),—NR^(19A)C(O)R^(19C), —NR^(19A)C(O)OR^(19C), —NR^(19A)OR^(19C), —OCX¹⁹₃, —OCHX¹⁹ ₂, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), substituted (e.g., substituted with a substituent group,a size-limited substituent group, or lower substituent group) orunsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). R^(16A),R^(16B), R^(16C), R^(16D), R^(17A), R^(17B), R^(17C), R^(17D), R^(18A),R^(18B), R^(18C), R^(18D), R^(19A), R^(19B), R^(19C), and R^(19D) areindependently hydrogen, halogen, —CX₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCX₃, —OCHX₂, —CHX₂,—CH₂X, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), substituted (e.g., substituted with a substituent group,a size-limited substituent group, or lower substituent group) orunsubstituted cycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R^(16A) and R^(16B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered) or substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R^(17A) andR^(17B) substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heterocycloalkyl (e.g., 3 to 10 membered, 3 to 8 membered,3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered)or substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered); R^(18A) and R^(18B) substituents bondedto the same nitrogen atom may optionally be joined to form a substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heterocycloalkyl(e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered) or substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heteroaryl (e.g., 5 to 12membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered);R^(19A) and R^(19B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl (e.g., 3 to 10membered, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered) or substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heteroaryl (e.g., 5 to 12 membered,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

Each X, X¹⁶, X¹⁷, X¹⁸ and X¹⁹ is independently —F, —Cl, —Br, or —I. Thesymbols n16, n17, n18, n19, v16, v17, v18, and v19 are independently aninteger from 0 to 4. The symbols m16, m17, m18, and m19 areindependently an integer from 1 to 2. In embodiments, R¹⁸ is —CN. Inembodiments, R¹⁶ is unsubstituted methyl. In embodiments, R¹⁷ isunsubstituted methyl. In embodiments, R¹⁸ is unsubstituted methyl. Inembodiments, R¹⁹ is unsubstituted methyl. In embodiments, R¹⁸ ishydrogen. In embodiments, R¹⁶ is hydrogen. In embodiments, R¹⁷ ishydrogen. In embodiments, R¹⁹ is hydrogen.

X may independently be —F. X may independently be —Cl. X mayindependently be —Br. X may independently be —I. X¹⁶ may independentlybe —F. X¹⁶ may independently be —Cl. X¹⁶ may independently be —Br. X¹⁶may independently be —I. X¹⁷ may independently be —F. X¹⁷ mayindependently be —Cl. X¹⁷ may independently be —Br. X¹⁷ mayindependently be —I. X¹⁸ may independently be —F. X¹⁸ may independentlybe —Cl. X¹⁸ may independently be —Br. X¹⁸ may independently be —I. X¹⁹may independently be —F. X¹⁹ may independently be —Cl. X¹⁹ mayindependently be —Br. X¹⁹ may independently be —I.

n16 may independently be 0. n16 may independently be 1. n16 mayindependently be 2. n16 may independently be 3. n16 may independently be4. n17 may independently be 0. n17 may independently be 1. n17 mayindependently be 2. n17 may independently be 3. n17 may independently be4. n18 may independently be 0. n18 may independently be 1. n18 mayindependently be 2. n18 may independently be 3. n18 may independently be4. n19 may independently be 0. n19 may independently be 1. n19 mayindependently be 2. n19 may independently be 3. n19 may independently be4.

v16 may independently be 0. v16 may independently be 1. v16 mayindependently be 2. v16 may independently be 3. v16 may independently be4. v17 may independently be 0. v17 may independently be 1. v17 mayindependently be 2. v17 may independently be 3. v17 may independently be4. v18 may independently be 0. v18 may independently be 1. v18 mayindependently be 2. v18 may independently be 3. v18 may independently be4. v19 may independently be 0. v19 may independently be 1. v19 mayindependently be 2. v19 may independently be 3. v19 may independently be4.

m16 may independently be 1. m16 may independently be 2. m17 mayindependently be 1. m17 may independently be 2. m18 may independentlybe 1. m18 may independently be 2. m19 may independently be 1. m19 mayindependently be 2.

In embodiments, R¹⁶ is hydrogen. In embodiments, R¹⁶ is halogen. Inembodiments, R¹⁶ is unsubstituted tert-butyl. In embodiments, R¹⁶ is—CH₂Ph. In embodiments, R¹⁶ is independently unsubstituted methyl. Inembodiments, R¹⁶ is independently unsubstituted ethyl. In embodiments,R¹⁶ is independently unsubstituted propyl. In embodiments, R¹⁶ isindependently unsubstituted n-propyl. In embodiments, R¹⁶ isindependently unsubstituted isopropyl. In embodiments, R¹⁶ isindependently unsubstituted butyl. In embodiments, R¹⁶ is independentlyunsubstituted n-butyl. In embodiments, R¹⁶ is independentlyunsubstituted isobutyl. In embodiments, R¹⁶ is independentlyunsubstituted tert-butyl. In embodiments, R¹⁶ is independentlyunsubstituted pentyl. In embodiments, R¹⁶ is independently unsubstitutedhexyl. In embodiments, R¹⁶ is independently unsubstituted heptyl. Inembodiments, R¹⁶ is independently unsubstituted octyl. In embodiments,R¹⁶ is independently —F. In embodiments, R¹⁶ is independently —Cl. Inembodiments, R¹⁶ is independently —Br. In embodiments, R¹⁶ isindependently —I. In embodiments, R¹⁶ is independently unsubstitutedmethoxy. In embodiments, R¹⁶ is independently unsubstituted ethoxy. Inembodiments, R¹⁶ is independently —CF₃. In embodiments, R¹⁶ isindependently —CCl₃. In embodiments, R¹⁶ is an unsubstituted isopropyl.In embodiments, R¹⁶ is an unsubstituted phenyl. In embodiments, R¹⁶ isan unsubstituted pyridyl. In embodiments, R¹⁶ is independently halogen.In embodiments, R¹⁶ is independently —CX¹⁶ ₃. In embodiments, R¹⁶ isindependently —CHX¹⁶ ₂. In embodiments, R¹⁶ is independently—CH₂X^(1.6). In embodiments, R¹⁶ is independently —CN. In embodiments,R¹⁶ is independently —OH. In embodiments, R¹⁶ is independently —NH₂. Inembodiments, R¹⁶ is independently —COOH. In embodiments, R¹⁶ isindependently —CONH₂. In embodiments, R¹⁶ is independently —NO₂. Inembodiments, R¹⁶ is independently —SH. In embodiments, R¹⁶ isindependently —SO₃H. In embodiments, R¹⁶ is independently —SO₄H. Inembodiments, R¹⁶ is independently —SO₂NH₂. In embodiments, R¹⁶ isindependently —NHNH₂. In embodiments, R¹⁶ is independently —ONH₂. Inembodiments, R¹⁶ is independently —NHC(O)NHNH₂. In embodiments, R¹⁶ isindependently —NHC(O)NH₂. In embodiments, R¹⁶ is independently —NHSO₂H.In embodiments, R¹⁶ is independently —NHC(O)H. In embodiments, R¹⁶ isindependently —NHC(O)OH. In embodiments, R¹⁶ is independently —NHOH. Inembodiments, R¹⁶ is independently —OCX¹⁶ ₃. In embodiments, R¹⁶ isindependently —OCHX¹⁶ ₂.

In embodiments, R^(16A) is hydrogen. In embodiments, R^(16A) is —CX₃. Inembodiments, R^(16A) is —CN. In embodiments, R^(16A) is —COOH. Inembodiments, R^(16A) is —CONH₂. In embodiments, R^(16A) is —CHX₂. Inembodiments, R^(16A) is —CH₂X. In embodiments, R^(16A) is unsubstitutedmethyl. In embodiments, R^(16A) is unsubstituted ethyl. In embodiments,R^(16A) is unsubstituted propyl. In embodiments, R^(16A) isunsubstituted isopropyl. In embodiments, R^(16A) is unsubstituted butyl.In embodiments, R^(16A) is unsubstituted tert-butyl.

In embodiments, R^(16B) is hydrogen. In embodiments, R^(16B) is —CX₃. Inembodiments, R^(16B) is —CN. In embodiments, R^(16B) is —COOH. Inembodiments, R^(16B) is —CONH₂. In embodiments, R^(16B) is —CHX₂. Inembodiments, R^(16B) is —CH₂X. In embodiments, R^(16B) is unsubstitutedmethyl. In embodiments, R^(16B) is unsubstituted ethyl. In embodiments,R^(16B) is unsubstituted propyl. In embodiments, R^(16B) isunsubstituted isopropyl. In embodiments, R^(16B) is unsubstituted butyl.In embodiments, R^(16B) is unsubstituted tert-butyl.

In embodiments, R^(16C) is hydrogen. In embodiments, R^(16C) is —CX₃. Inembodiments, R^(16C) is —CN. In embodiments, R^(16C) is —COOH. Inembodiments, R^(16C) is —CONH₂. In embodiments, R^(16C) is —CHX₂. Inembodiments, R^(16C) is —CH₂X. In embodiments, R^(16C) is unsubstitutedmethyl. In embodiments, R^(16C) is unsubstituted ethyl. In embodiments,R^(16C) is unsubstituted propyl. In embodiments, R^(16C) isunsubstituted isopropyl. In embodiments, R^(16C) is unsubstituted butyl.In embodiments, R^(16C) is unsubstituted tert-butyl.

In embodiments, R^(16D) is hydrogen. In embodiments, R^(16D) is —CX₃. Inembodiments, R^(16D) is —CN. In embodiments, R^(16D) is —COOH. Inembodiments, R^(16D) is —CONH₂. In embodiments, R^(16D) is —CHX₂. Inembodiments, R^(16D) is —CH₂X. In embodiments, R^(16D) is unsubstitutedmethyl. In embodiments, R^(16D) is unsubstituted ethyl. In embodiments,R^(16D) is unsubstituted propyl. In embodiments, R^(16D) isunsubstituted isopropyl. In embodiments, R^(16D) is unsubstituted butyl.In embodiments, R^(16D) is unsubstituted tert-butyl.

In embodiments, R¹⁷ is hydrogen. In embodiments, R¹⁷ is halogen. Inembodiments, R¹⁷ is unsubstituted tert-butyl. In embodiments, R¹⁷ is—CH₂Ph. In embodiments, R¹⁷ is independently unsubstituted methyl. Inembodiments, R¹⁷ is independently unsubstituted ethyl. In embodiments,R¹⁷ is independently unsubstituted propyl. In embodiments, R¹⁷ isindependently unsubstituted n-propyl. In embodiments, R¹⁷ isindependently unsubstituted isopropyl. In embodiments, R¹⁷ isindependently unsubstituted butyl. In embodiments, R¹⁷ is independentlyunsubstituted n-butyl. In embodiments, R¹⁷ is independentlyunsubstituted isobutyl. In embodiments, R¹⁷ is independentlyunsubstituted tert-butyl. In embodiments, R¹⁷ is independentlyunsubstituted pentyl. In embodiments, R¹⁷ is independently unsubstitutedhexyl. In embodiments, R¹⁷ is independently unsubstituted heptyl. Inembodiments, R¹⁷ is independently unsubstituted octyl. In embodiments,R¹⁷ is independently —F. In embodiments, R¹⁷ is independently —Cl. Inembodiments, R¹⁷ is independently —Br. In embodiments, R¹⁷ isindependently —I. In embodiments, R¹⁷ is independently unsubstitutedmethoxy. In embodiments, R¹⁷ is independently unsubstituted ethoxy. Inembodiments, R¹⁷ is independently —CF₃. In embodiments, R¹⁷ isindependently —CCl₃. In embodiments, R¹⁷ is an unsubstituted isopropyl.In embodiments, R¹⁷ is an unsubstituted phenyl. In embodiments, R¹⁷ isan unsubstituted pyridyl. In embodiments, R¹⁷ is independently halogen.In embodiments, R¹⁷ is independently —CX¹⁷ ₃. In embodiments, R¹⁷ isindependently —CHX¹⁷ ₂. In embodiments, R¹⁷ is independently—CH₂X^(1.7). In embodiments, R¹⁷ is independently —CN. In embodiments,R¹⁷ is independently —OH. In embodiments, R¹⁷ is independently —NH₂. Inembodiments, R¹⁷ is independently —COOH. In embodiments, R¹⁷ isindependently —CONH₂. In embodiments, R¹⁷ is independently —NO₂. Inembodiments, R¹⁷ is independently —SH. In embodiments, R¹⁷ isindependently —SO₃H. In embodiments, R¹⁷ is independently —SO₄H. Inembodiments, R¹⁷ is independently —SO₂NH₂. In embodiments, R¹⁷ isindependently —NHNH₂. In embodiments, R¹⁷ is independently —ONH₂. Inembodiments, R¹⁷ is independently —NHC(O)NHNH₂. In embodiments, R¹⁷ isindependently —NHC(O)NH₂. In embodiments, R¹⁷ is independently —NHSO₂H.In embodiments, R¹⁷ is independently —NHC(O)H. In embodiments, R¹⁷ isindependently —NHC(O)OH. In embodiments, R¹⁷ is independently —NHOH. Inembodiments, R¹⁷ is independently —OCX¹⁷ ₃. In embodiments, R¹⁷ isindependently —OCHX¹⁷ ₂.

In embodiments, R^(17A) is hydrogen. In embodiments, R^(17A) is —CX₃. Inembodiments, R^(17A) is —CN. In embodiments, R^(17A) is —COOH. Inembodiments, R^(17A) is —CONH₂. In embodiments, R^(17A) is —CHX₂. Inembodiments, R^(17A) is —CH₂X. In embodiments, R^(17A) is unsubstitutedmethyl. In embodiments, R^(17A) is unsubstituted ethyl. In embodiments,R^(17A) is unsubstituted propyl. In embodiments, R^(17A) isunsubstituted isopropyl. In embodiments, R^(17A) is unsubstituted butyl.In embodiments, R^(17A) is unsubstituted tert-butyl.

In embodiments, R^(17B) is hydrogen. In embodiments, R^(17B) is —CX₃. Inembodiments, R^(17B) is —CN. In embodiments, R^(17B) is —COOH. Inembodiments, R^(17B) is —CONH₂. In embodiments, R^(17B) is —CHX₂. Inembodiments, R^(17B) is —CH₂X. In embodiments, R^(17B) is unsubstitutedmethyl. In embodiments, R^(17B) is unsubstituted ethyl. In embodiments,R^(17B) is unsubstituted propyl. In embodiments, R^(17B) isunsubstituted isopropyl. In embodiments, R^(17B) is unsubstituted butyl.In embodiments, R^(17B) is unsubstituted tert-butyl.

In embodiments, R^(17C) is hydrogen. In embodiments, R^(17C) is —CX₃. Inembodiments, R^(17C) is —CN. In embodiments, R^(17C) is —COOH. Inembodiments, R^(17C) is —CONH₂. In embodiments, R^(17C) is —CHX₂. Inembodiments, R^(17C) is —CH₂X. In embodiments, R^(17C) is unsubstitutedmethyl. In embodiments, R^(17C) is unsubstituted ethyl. In embodiments,R^(17C) is unsubstituted propyl. In embodiments, R^(17C) isunsubstituted isopropyl. In embodiments, R^(17C) is unsubstituted butyl.In embodiments, R^(17C) is unsubstituted tert-butyl.

In embodiments, R^(17D) is hydrogen. In embodiments, R^(17D) is —CX₃. Inembodiments, R^(17D) is —CN. In embodiments, R^(17D) is —COOH. Inembodiments, R^(17D) is —CONH₂. In embodiments, R^(17D) is —CHX₂. Inembodiments, R^(17D) is —CH₂X. In embodiments, R^(17D) is unsubstitutedmethyl. In embodiments, R^(17D) is unsubstituted ethyl. In embodiments,R^(17D) is unsubstituted propyl. In embodiments, R^(17D) isunsubstituted isopropyl. In embodiments, R^(17D) is unsubstituted butyl.In embodiments, R^(17D) is unsubstituted tert-butyl.

In embodiments, R¹⁸ is hydrogen. In embodiments, R¹⁸ is halogen. Inembodiments, R¹⁸ is unsubstituted tert-butyl. In embodiments, R¹⁸ is—CH₂Ph. In embodiments, R¹⁸ is independently unsubstituted methyl. Inembodiments, R¹⁸ is independently unsubstituted ethyl. In embodiments,R¹⁸ is independently unsubstituted propyl. In embodiments, R¹⁸ isindependently unsubstituted n-propyl. In embodiments, R¹⁸ isindependently unsubstituted isopropyl. In embodiments, R¹⁸ isindependently unsubstituted butyl. In embodiments, R¹⁸ is independentlyunsubstituted n-butyl. In embodiments, R¹⁸ is independentlyunsubstituted isobutyl. In embodiments, R¹⁸ is independentlyunsubstituted tert-butyl. In embodiments, R¹⁸ is independentlyunsubstituted pentyl. In embodiments, R¹⁸ is independently unsubstitutedhexyl. In embodiments, R¹⁸ is independently unsubstituted heptyl. Inembodiments, R¹⁸ is independently unsubstituted octyl. In embodiments,R¹⁸ is independently —F. In embodiments, R¹⁸ is independently —Cl. Inembodiments, R¹⁸ is independently —Br. In embodiments, R¹⁸ isindependently —I. In embodiments, R¹⁸ is independently unsubstitutedmethoxy. In embodiments, R¹⁸ is independently unsubstituted ethoxy. Inembodiments, R¹⁸ is independently —CF₃. In embodiments, R¹⁸ isindependently —CCl₃. In embodiments, R¹⁸ is an unsubstituted isopropyl.In embodiments, R¹⁸ is an unsubstituted phenyl. In embodiments, R¹⁸ isan unsubstituted pyridyl. In embodiments, R¹⁸ is independently halogen.In embodiments, R¹⁸ is independently —CX¹⁸ ₃. In embodiments, R¹⁸ isindependently —CHX¹⁸ ₂. In embodiments, R¹⁸ is independently —CH₂X¹⁸. Inembodiments, R¹⁸ is independently —CN. In embodiments, R¹⁸ isindependently —OH. In embodiments, R¹⁸ is independently —NH₂. Inembodiments, R¹⁸ is independently —COOH. In embodiments, R¹⁸ isindependently —CONH₂. In embodiments, R¹⁸ is independently —NO₂. Inembodiments, R¹⁸ is independently —SH. In embodiments, R¹⁸ isindependently —SO₃H. In embodiments, R¹⁸ is independently —SO₄H. Inembodiments, R¹⁸ is independently —SO₂NH₂. In embodiments, R¹⁸ isindependently —NHNH₂. In embodiments, R¹⁸ is independently —ONH₂. Inembodiments, R¹⁸ is independently —NHC(O)NHNH₂. In embodiments, R¹⁸ isindependently —NHC(O)NH₂. In embodiments, R¹⁸ is independently —NHSO₂H.In embodiments, R¹⁸ is independently —NHC(O)H. In embodiments, R¹⁸ isindependently —NHC(O)OH. In embodiments, R¹⁸ is independently —NHOH. Inembodiments, R¹⁸ is independently —OCX¹⁸ ₃. In embodiments, R¹⁸ isindependently —OCHX¹⁸ ₂.

In embodiments, R^(18A) is hydrogen. In embodiments, R^(18A) is —CX₃. Inembodiments, R^(18A) is —CN. In embodiments, R^(18A) is —COOH. Inembodiments, R^(18A) is —CONH₂. In embodiments, R^(18A) is —CHX₂. Inembodiments, R^(18A) is —CH₂X. In embodiments, R^(18A) is unsubstitutedmethyl. In embodiments, R^(18A) is unsubstituted ethyl. In embodiments,R^(18A) is unsubstituted propyl. In embodiments, R^(18A) isunsubstituted isopropyl. In embodiments, R^(18A) is unsubstituted butyl.In embodiments, R^(18A) is unsubstituted tert-butyl.

In embodiments, R^(18B) is hydrogen. In embodiments, R^(18B) is —CX₃. Inembodiments, R^(18B) is —CN. In embodiments, R^(18B) is —COOH. Inembodiments, R^(18B) is —CONH₂. In embodiments, R^(18B) is —CHX₂. Inembodiments, R^(18B) is —CH₂X. In embodiments, R^(18B) is unsubstitutedmethyl. In embodiments, R^(18B) is unsubstituted ethyl. In embodiments,R^(18B) is unsubstituted propyl. In embodiments, R^(18B) isunsubstituted isopropyl. In embodiments, R^(18B) is unsubstituted butyl.In embodiments, R^(18B) is unsubstituted tert-butyl.

In embodiments, R^(18C) is hydrogen. In embodiments, R^(18C) is —CX₃. Inembodiments, R^(18C) is —CN. In embodiments, R^(18C) is —COOH. Inembodiments, R^(18C) is —CONH₂. In embodiments, R^(18C) is —CHX₂. Inembodiments, R^(18C) is —CH₂X. In embodiments, R^(18C) is unsubstitutedmethyl. In embodiments, R^(18C) is unsubstituted ethyl. In embodiments,R^(18C) is unsubstituted propyl. In embodiments, R^(18C) isunsubstituted isopropyl. In embodiments, R^(18C) is unsubstituted butyl.In embodiments, R^(18C) is unsubstituted tert-butyl.

In embodiments, R^(18D) is hydrogen. In embodiments, R^(18D) is —CX₃. Inembodiments, R^(18D) is —CN. In embodiments, R^(18D) is —COOH. Inembodiments, R^(18D) is —CONH₂. In embodiments, R^(18D) is —CHX₂. Inembodiments, R^(18D) is —CH₂X. In embodiments, R^(18D) is unsubstitutedmethyl. In embodiments, R^(18D) is unsubstituted ethyl. In embodiments,R^(18D) is unsubstituted propyl. In embodiments, R^(18D) isunsubstituted isopropyl. In embodiments, R^(18D) is unsubstituted butyl.In embodiments, R^(18D) is unsubstituted tert-butyl.

In embodiments, R¹⁹ is hydrogen. In embodiments, R¹⁹ is halogen. Inembodiments, R¹⁹ is unsubstituted tert-butyl. In embodiments, R¹⁹ is—CH₂Ph. In embodiments, R¹⁹ is independently unsubstituted methyl. Inembodiments, R¹⁹ is independently unsubstituted ethyl. In embodiments,R¹⁹ is independently unsubstituted propyl. In embodiments, R¹⁹ isindependently unsubstituted n-propyl. In embodiments, R¹⁹ isindependently unsubstituted isopropyl. In embodiments, R¹⁹ isindependently unsubstituted butyl. In embodiments, R¹⁹ is independentlyunsubstituted n-butyl. In embodiments, R¹⁹ is independentlyunsubstituted isobutyl. In embodiments, R¹⁹ is independentlyunsubstituted tert-butyl. In embodiments, R¹⁹ is independentlyunsubstituted pentyl. In embodiments, R¹⁹ is independently unsubstitutedhexyl. In embodiments, R¹⁹ is independently unsubstituted heptyl. Inembodiments, R¹⁹ is independently unsubstituted octyl. In embodiments,R¹⁹ is independently —F. In embodiments, R¹⁹ is independently —Cl. Inembodiments, R¹⁹ is independently —Br. In embodiments, R¹⁹ isindependently —I. In embodiments, R¹⁹ is independently unsubstitutedmethoxy. In embodiments, R¹⁹ is independently unsubstituted ethoxy. Inembodiments, R¹⁹ is independently —CF₃. In embodiments, R¹⁹ isindependently —CCl₃. In embodiments, R¹⁹ is an unsubstituted isopropyl.In embodiments, R¹⁹ is an unsubstituted phenyl. In embodiments, R¹⁹ isan unsubstituted pyridyl. In embodiments, R¹⁹ is independently halogen.In embodiments, R¹⁹ is independently —CX¹⁹ ₃. In embodiments, R¹⁹ isindependently —CHX¹⁹ ₂. In embodiments, R¹⁹ is independently —CH₂X¹⁹. Inembodiments, R¹⁹ is independently —CN. In embodiments, R¹⁹ isindependently —OH. In embodiments, R¹⁹ is independently —NH₂. Inembodiments, R¹⁹ is independently —COOH. In embodiments, R¹⁹ isindependently —CONH₂. In embodiments, R¹⁹ is independently —NO₂. Inembodiments, R¹⁹ is independently —SH. In embodiments, R¹⁹ isindependently —SO₃H. In embodiments, R¹⁹ is independently —SO₄H. Inembodiments, R¹⁹ is independently —SO₂NH₂. In embodiments, R¹⁹ isindependently —NHNH₂. In embodiments, R¹⁹ is independently —ONH₂. Inembodiments, R¹⁹ is independently —NHC(O)NHNH₂. In embodiments, R¹⁹ isindependently —NHC(O)NH₂. In embodiments, R¹⁹ is independently —NHSO₂H.In embodiments, R¹⁹ is independently —NHC(O)H. In embodiments, R¹⁹ isindependently —NHC(O)OH. In embodiments, R¹⁹ is independently —NHOH. Inembodiments, R¹⁹ is independently —OCX¹⁹ ₃. In embodiments, R¹⁹ isindependently —OCHX¹⁹ ₂.

In embodiments, R^(19A) is hydrogen. In embodiments, R^(19A) is —CX₃. Inembodiments, R^(19A) is —CN. In embodiments, R^(19A) is —COOH. Inembodiments, R^(19A) is —CONH₂. In embodiments, R^(19A) is —CHX₂. Inembodiments, R^(19A) is —CH₂X. In embodiments, R^(19A) is unsubstitutedmethyl. In embodiments, R^(19A) is unsubstituted ethyl. In embodiments,R^(19A) is unsubstituted propyl. In embodiments, R^(19A) isunsubstituted isopropyl. In embodiments, R^(19A) is unsubstituted butyl.In embodiments, R^(19A) is unsubstituted tert-butyl.

In embodiments, R^(19B) is hydrogen. In embodiments, R^(19B) is —CX₃. Inembodiments, R^(19B) is —CN. In embodiments, R^(19B) is —COOH. Inembodiments, R^(19B) is —CONH₂. In embodiments, R^(19B) is —CHX₂. Inembodiments, R^(19B) is —CH₂X. In embodiments, R^(19B) is unsubstitutedmethyl. In embodiments, R^(19B) is unsubstituted ethyl. In embodiments,R^(19B) is unsubstituted propyl. In embodiments, R^(19B) isunsubstituted isopropyl. In embodiments, R^(19B) is unsubstituted butyl.In embodiments, R^(19B) is unsubstituted tert-butyl.

In embodiments, R^(19C) is hydrogen. In embodiments, R^(19C) is —CX₃. Inembodiments, R^(19C) is —CN. In embodiments, R^(19C) is —COOH. Inembodiments, R^(19C) is —CONH₂. In embodiments, R^(19C) is —CHX₂. Inembodiments, R^(19C) is —CH₂X. In embodiments, R^(19C) is unsubstitutedmethyl. In embodiments, R^(19C) is unsubstituted ethyl. In embodiments,R^(19C) is unsubstituted propyl. In embodiments, R^(19C) isunsubstituted isopropyl. In embodiments, R^(19C) is unsubstituted butyl.In embodiments, R^(19C) is unsubstituted tert-butyl.

In embodiments, R^(19D) is hydrogen. In embodiments, R^(19D) is —CX₃. Inembodiments, R^(19D) is —CN. In embodiments, R^(19D) is —COOH. Inembodiments, R^(19D)is —CONH₂. In embodiments, R^(19D) is —CHX₂. Inembodiments, R^(19D) is —CH₂X. In embodiments, R^(19D) is unsubstitutedmethyl. In embodiments, R^(19D) is unsubstituted ethyl. In embodiments,R^(19D) is unsubstituted propyl. In embodiments, R^(19D) isunsubstituted isopropyl. In embodiments, R^(19D) is unsubstituted butyl.In embodiments, R^(19D) is unsubstituted tert-butyl.

In embodiments, E includes a substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted vinyl sulfone moiety, substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted vinyl sulfonamidemoiety, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted fluoro(C₁-C₄)alkylketone moiety, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted chloro(C₁-C₄)alkylketonemoiety, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted acrylamide moiety, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted disulfide moiety, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted thiol moiety, substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted phosphonate moiety,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted aldehydemoiety, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted enone moiety, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted diazomethylketone moiety,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituteddiazomethylamide moiety, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cyanocyclopropyl carboxamide moiety,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted epoxidemoiety, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted epoxyketone moiety, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted epoxyamide moiety, substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted aryl aldehydemoiety, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted aryl dialdehyde moiety, substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted dialdehyde moiety, substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted nitrogen mustardmoiety, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted propargyl moiety, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted propargylamide moiety,

In embodiments, E is a substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted vinyl sulfone moiety, substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted vinyl sulfonamide moiety,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedfluoro(C₁-C₄)alkylketone moiety, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted chloro(C₁-C₄)alkylketone moiety,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedacrylamide moiety, substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted disulfide moiety, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted thiol moiety, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted phosphonate moiety,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted aldehydemoiety, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted enone moiety, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted diazomethylketone moiety,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituteddiazomethylamide moiety, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cyanocyclopropyl carboxamide moiety,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted epoxidemoiety, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted epoxyketone moiety, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted epoxyamide moiety, substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted aryl aldehydemoiety, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted aryl dialdehyde moiety, substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted dialdehyde moiety, substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted nitrogen mustardmoiety, substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted propargyl moiety, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted propargylamide moiety,

In embodiments, E is an unsubstituted vinyl sulfone moiety,unsubstituted vinyl sulfonamide moiety, unsubstitutedfluoro(C₁-C₄)alkylketone moiety, unsubstituted chloro(C₁-C₄)alkylketonemoiety, unsubstituted acrylamide moiety, unsubstituted disulfide moiety,unsubstituted thiol moiety, unsubstituted phosphonate moiety,unsubstituted aldehyde moiety, unsubstituted enone moiety, unsubstituteddiazomethylketone moiety, unsubstituted diazomethylamide moiety,unsubstituted cyanocyclopropyl carboxamide moiety, unsubstituted epoxidemoiety, unsubstituted epoxyketone moiety, unsubstituted epoxyamidemoiety, unsubstituted aryl aldehyde moiety, unsubstituted aryldialdehyde moiety, unsubstituted dialdehyde moiety, unsubstitutednitrogen mustard moiety, unsubstituted propargyl moiety, orunsubstituted propargylamide moiety.

R¹³ is independently hydrogen, a substituent group, a size-limitedsubstituent group, or a lower substituent group. In embodiments, R¹³ isindependently hydrogen.

In embodiments, the compound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴ and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein.In embodiments, the compound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L⁴, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein. In embodiments,the compound is

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein.In embodiments, the compound is

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein. In embodiments,the compound is

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein. In embodiments,the compound is

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein.In embodiments, the compound is

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein. In embodiments,the compound is

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein. In embodiments,the compound is

wherein R¹, L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is

wherein R^(1.3), R^(1.1), R^(1.3), L³, L⁴, and R⁵ L³, L⁴, and R⁵ are asdescribed herein. In embodiments, the compound is

wherein R^(1.2), R^(1.4), L³, L⁴, and R⁵ are as described herein.In embodiments, the compound is

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein. In embodiments,the compound is

wherein R^(1.3), R^(1.5), L³, L⁴, and R⁵ are as described herein. Inembodiments, the compound is

wherein R^(1.3), L³, L⁴, and R⁵ are as described herein. In embodiments,the compound is

wherein R^(1.3), R^(1.4), L³, L⁴, and R⁵ are as described herein. Inembodiments, the compound is

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein. In embodiments,the compound is

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein.

In embodiments, unless otherwise indicated, a compound described hereinis a racemic mixture of all stereoisomers. In embodiments, unlessotherwise indicated, a compound described herein is a racemic mixture ofall enantiomers. In embodiments, unless otherwise indicated, a compounddescribed herein is a racemic mixture of two opposite stereoisomers. Inembodiments, unless otherwise indicated, a compound described herein isa racemic mixture of two opposite enantiomers. In embodiments, unlessotherwise indicated, a compound described herein is a singlestereoisomer. In embodiments, unless otherwise indicated, a compounddescribed herein is a single enantiomer.

In embodiments, the compound inhibits proliferation of cancer cellsunder nutrient deficient conditions relative to the absence of thecompound. In embodiments, the compound inhibits growth of cancer cellsunder nutrient deficient conditions relative to the absence of thecompound. In embodiments, the compound inhibits growth of cancer cellsunder nutrient deficient conditions relative to the absence of thecompound. In embodiments, the compound inhibits growth of cancer cellsunder serum deprivation conditions relative to the absence of thecompound. In embodiments, the compound inhibits proliferation of cancercells under serum deprivation conditions relative to the absence of thecompound. In embodiments, the compound inhibits growth of cancer cellsunder conditions (e.g. local cell environment in a patient) mimickingserum deprivation relative to the absence of the compound. Inembodiments, the compound inhibits proliferation of cancer cells underconditions (e.g. local cell environment in a patient) mimicking serumdeprivation relative to the absence of the compound.

In some embodiments, the compound is any one of the compounds describedherein (e.g., in an aspect, embodiment, claim, figure, table, orexample).

In some embodiments, a compound as described herein may include multipleinstances of R¹ and/or other variables. In such embodiments, eachvariable may optional be different and be appropriately labeled todistinguish each group for greater clarity. For example, where each R¹,is different, they may be referred to, for example, as R^(1.1), R^(1.2),R^(1.3), R^(1.4), R^(1.5), respectively, wherein the definition of R¹ isassumed by R^(1.1), R^(1.2), R^(1.3), R^(1.4), R^(1.5).

The variables used within a definition of R¹ and/or other variables thatappear at multiple instances and are different may similarly beappropriately labeled to distinguish each group for greater clarity.

In embodiments, the compound is 966844. In embodiments, the compound is966854. In embodiments, the compound is 917181. In embodiments, thecompound is 917105. In embodiments, the compound is 960005. Inembodiments, the compound is 917332. In embodiments, the compound is916860. In embodiments, the compound is 916929. In embodiments, thecompound is 917680. In embodiments, the compound is 917876. Inembodiments, the compound is 957805. In embodiments, the compound is966844. In embodiments, the compound is 966849. In embodiments, thecompound is 966794. In embodiments, the compound is 966854. Inembodiments, the compound is 957833. In embodiments, the compound is916860. In embodiments, the compound is 917105. In embodiments, thecompound is 917181. In embodiments, the compound is 966976. Inembodiments, the compound is 917162. In embodiments, the compound is916929. In embodiments, the compound is 957805. In embodiments, thecompound is 916960. In embodiments, the compound is 996844. Inembodiments, the compound is 996849. In embodiments, the compound is996854. In embodiments, the compound is 717105. In embodiments, thecompound is 916929. In embodiments, the compound is 966844. Inembodiments, the compound is 966854. In embodiments, the compound is966849. In embodiments, the compound is 917105. In embodiments, thecompound is 916929. In embodiments, the compound is FNL-002. Inembodiments, the compound is FNL-0006. In embodiments, the compound isFNL-0007. In embodiments, the compound is FNL-0008. In embodiments, thecompound is FNL-0004. In embodiments, the compound is FNL-0005. Inembodiments, the compound is FNL-0009. In embodiments, the compound isFNL-0001. In embodiments, the compound is FNL-0013. In embodiments, thecompound is FNL-00014. In embodiments, the compound is FNL-0015. Inembodiments, the compound is FNL-0024. In embodiments, the compound isFNL-0026. In embodiments, the compound is FNL-0016. In embodiments, thecompound is FNL-0010. In embodiments, the compound is FNL-0012. Inembodiments, the compound is FNL-0030. In embodiments, the compound isFNL-0036. In embodiments, the compound is FNL-0037. In embodiments, thecompound is FNL-0038.

In embodiments, the compound is SMDC 917105. In embodiments, thecompound is SMDC 917102. In embodiments, the compound is SMDC 916899. Inembodiments, the compound is SMDC 917181. In embodiments, the compoundis SMDC 916860. In embodiments, the compound is SMDC 916860. Inembodiments, the compound is SMDC 966906. In embodiments, the compoundis SMDC 917138. In embodiments, the compound is SMDC 960055. Inembodiments, the compound is SMDC 966921. In embodiments, the compoundis SMDC 966976. In embodiments, the compound is SMDC 917632. Inembodiments, the compound is SMDC917192. In embodiments, the compound isSMDC 966938. In embodiments, the compound is SMDC 957780. Inembodiments, the compound is SMDC 966844. In embodiments, the compoundis SMDC 966854. In embodiments, the compound is SMDC 966782. Inembodiments, the compound is SMDC 966849. In embodiments, the compoundis SMDC 966859. In embodiments, the compound is SMDC 966539. Inembodiments, the compound is SMDC 966781. In embodiments, the compoundis SMDC 966846. In embodiments, the compound is SMDC 957828. Inembodiments, the compound is SMDC 966783. In embodiments, the compoundis SMDC966536. In embodiments, the compound is SMDC 966541. Inembodiments, the compound is SMDC 966794. In embodiments, the compoundis SMDC 966793. In embodiments, the compound is SMDC 966785. Inembodiments, the compound is SMDC 966538. In embodiments, the compoundis SMDC 966858. In embodiments, the compound is SMDC 966857. Inembodiments, the compound is SMDC 966789. In embodiments, the compoundis SMDC 957835. In embodiments, the compound is SMDC 957827. Inembodiments, the compound is SMDC 966844. In embodiments, the compoundis SMDC 916860. In embodiments, the compound is SMDC 917162. Inembodiments, the compound is SMDC 966849. In embodiments, the compoundis SMDC 917105. In embodiments, the compound is SMDC 916929. Inembodiments, the compound is SMDC 996794. In embodiments, the compoundis SMDC 917181. In embodiments, the compound is SMDC 966854. Inembodiments, the compound is SMDC 966976. In embodiments, the compoundis SMDC 957805. In embodiments, the compound is SMDC 957833. Inembodiments, the compound is SMDC 916960.

In embodiments, the compound is not a compound described in an example,figure, table, or scheme. In embodiments, the compound is not a compounddescribed in WO 2016/179558, which is incorporated by reference for anypurpose.

In embodiments, R⁵ is not

In embodiments, R⁵ does not include a disulfide bridge moiety. Inembodiments, R⁵ is not

In embodiments, R⁵ is not

In embodiments, R⁵ is not

In embodiments, -L³-L⁴-R⁵ is not

In embodiments, -L³-L⁴-R⁵ is not

In embodiments, -L³-L⁴-R⁵ is not

In embodiments, -L³-L⁴-R⁵ is not

In embodiments, -L³-L⁴-R⁵ is not

In embodiments, -L³-L⁴-R⁵ is not

In embodiments, E is not

In embodiments, E does not include a disulfide bridge moiety. Inembodiments, E is not

In embodiments, E is not

In embodiments, E is not

In embodiments, -L³-L⁴-E is not

In embodiments, -L³-L⁴-E is not

In embodiments, -L³-L⁴-E is not

In embodiments, -L³-L⁴-E is not

In embodiments, -L³-L⁴E is not

In embodiments, -L³-L⁴-E is not

In embodiments, the compound is not

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein. In embodiments,the compound is not

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein.In embodiments, the compound is not

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein. In embodiments,the compound is not

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein. In embodiments,the compound is not

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein. In embodiments,the compound is not

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein. In embodiments,the compound is not

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein. In embodiments,the compound is not

wherein R¹, L³, L⁴, and R⁵ are as described herein. In embodiments, thecompound is not

wherein R^(1.3), R^(1.1), R^(1.3), L³, L⁴, and R⁵ L³, L⁴, and R⁵ are asdescribed herein. In embodiments, the compound is not

wherein R^(1.2), R^(1.4), L³, L⁴, and R⁵ are as described herein.In embodiments, the compound is not

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein. In embodiments,the compound is not

wherein R^(1.3), R^(1.5), L³, L⁴, and R⁵ are as described herein. Inembodiments, the compound is not

wherein R^(1.3), R^(1.5), L³, L⁴, and R⁵ are as described herein. Inembodiments, the compound is not

wherein R^(1.3), R^(1.4), L³, L⁴, and R⁵ are as described herein. Inembodiments, the compound is not

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein. In embodiments,the compound is not

wherein R¹, z1, L³, L⁴, and R⁵ are as described herein. In embodiments,the compound is not

wherein R¹ and z1 are as described herein. In embodiments, the compoundis not

wherein R¹ and z1 are as described herein. In embodiments, the compoundis not

wherein R¹ and z1 are as described herein. In embodiments, the compoundis not

wherein R¹ and z1 are as described herein. In embodiments, the compoundis not

wherein R¹ and z1 are as described herein. In embodiments, the compoundis not

wherein R¹ and z1 are as described herein. In embodiments, the compoundis not

wherein R¹ and z1 are as described herein. In embodiments, the compoundis not

wherein R¹ is as described herein. In embodiments, the compound is not

wherein R^(1.1) and R^(1.3) are as described herein. In embodiments, thecompound is not

wherein R^(1.2) and R^(1.4) are as described herein.In embodiments, the compound is not

wherein R¹ and z1 are as described herein. In embodiments, the compoundis not

wherein R^(1.3) and R^(1.5) are as described herein. In embodiments, thecompound is not

R^(1.3) wherein R^(1.3) is as described herein. In embodiments, thecompound is not

wherein R^(1.3) and R^(1.4) are as described herein. In embodiments, thecompound is not

wherein R¹ and z1 are as described herein. In embodiments, the compoundis not

wherein R¹ and z1 are as described herein.

In embodiments, the compound is not 966844. In embodiments, the compoundis not 966854. In embodiments, the compound is not 917181. Inembodiments, the compound is not 917105. In embodiments, the compound isnot 960005. In embodiments, the compound is not 917332. In embodiments,the compound is not 916860. In embodiments, the compound is not 916929.In embodiments, the compound is not 917680. In embodiments, the compoundis not 917876. In embodiments, the compound is not 957805. Inembodiments, the compound is not 966844. In embodiments, the compound isnot 966849. In embodiments, the compound is not 966794. In embodiments,the compound is not 966854. In embodiments, the compound is not 957833.In embodiments, the compound is not 916860. In embodiments, the compoundis not 917105. In embodiments, the compound is not 917181. Inembodiments, the compound is not 966976. In embodiments, the compound isnot 917162. In embodiments, the compound is not 916929. In embodiments,the compound is not 957805. In embodiments, the compound is not 916960.In embodiments, the compound is not 996844. In embodiments, the compoundis not 996849. In embodiments, the compound is not 996854. Inembodiments, the compound is not 717105. In embodiments, the compound isnot 916929. In embodiments, the compound is not 966844. In embodiments,the compound is not 966854. In embodiments, the compound is not 966849.In embodiments, the compound is not 917105. In embodiments, the compoundis not 916929. In embodiments, the compound is not FNL-002. Inembodiments, the compound is not FNL-0006. In embodiments, the compoundis not FNL-0007. In embodiments, the compound is not FNL-0008. Inembodiments, the compound is not FNL-0004. In embodiments, the compoundis not FNL-0005. In embodiments, the compound is not FNL-0009. Inembodiments, the compound is not FNL-0001. In embodiments, the compoundis not FNL-0013. In embodiments, the compound is not FNL-00014. Inembodiments, the compound is not FNL-0015. In embodiments, the compoundis not FNL-0024. In embodiments, the compound is not FNL-0026. Inembodiments, the compound is not FNL-0016. In embodiments, the compoundis not FNL-0010. In embodiments, the compound is not FNL-0012. Inembodiments, the compound is not FNL-0030. In embodiments, the compoundis not FNL-0036. In embodiments, the compound is not FNL-0037. Inembodiments, the compound is not FNL-0038.

In embodiments, the compound is not 966844 or an analog or prodrugthereof. In embodiments, the compound is not 966854 or an analog orprodrug thereof. In embodiments, the compound is not 917181 or an analogor prodrug thereof. In embodiments, the compound is not 917105 or ananalog or prodrug thereof. In embodiments, the compound is not 960005 oran analog or prodrug thereof. In embodiments, the compound is not 917332or an analog or prodrug thereof. In embodiments, the compound is not916860 or an analog or prodrug thereof. In embodiments, the compound isnot 916929 or an analog or prodrug thereof. In embodiments, the compoundis not 917680 or an analog or prodrug thereof. In embodiments, thecompound is not 917876 or an analog or prodrug thereof. In embodiments,the compound is not 957805 or an analog or prodrug thereof. Inembodiments, the compound is not 966844 or an analog or prodrug thereof.In embodiments, the compound is not 966849 or an analog or prodrugthereof. In embodiments, the compound is not 966794 or an analog orprodrug thereof. In embodiments, the compound is not 966854 or an analogor prodrug thereof. In embodiments, the compound is not 957833 or ananalog or prodrug thereof. In embodiments, the compound is not 916860 oran analog or prodrug thereof. In embodiments, the compound is not 917105or an analog or prodrug thereof. In embodiments, the compound is not917181 or an analog or prodrug thereof. In embodiments, the compound isnot 966976 or an analog or prodrug thereof. In embodiments, the compoundis not 917162 or an analog or prodrug thereof. In embodiments, thecompound is not 916929 or an analog or prodrug thereof. In embodiments,the compound is not 957805 or an analog or prodrug thereof. Inembodiments, the compound is not 916960 or an analog or prodrug thereof.In embodiments, the compound is not 996844 or an analog or prodrugthereof. In embodiments, the compound is not 996849 or an analog orprodrug thereof. In embodiments, the compound is not 996854 or an analogor prodrug thereof. In embodiments, the compound is not 717105 or ananalog or prodrug thereof. In embodiments, the compound is not 916929 oran analog or prodrug thereof. In embodiments, the compound is not 966844or an analog or prodrug thereof. In embodiments, the compound is not966854 or an analog or prodrug thereof. In embodiments, the compound isnot 966849 or an analog or prodrug thereof. In embodiments, the compoundis not 917105 or an analog or prodrug thereof. In embodiments, thecompound is not 916929 or an analog or prodrug thereof. In embodiments,the compound is not FNL-002 or an analog or prodrug thereof. Inembodiments, the compound is not FNL-0006 or an analog or prodrugthereof. In embodiments, the compound is not FNL-0007 or an analog orprodrug thereof. In embodiments, the compound is not FNL-0008 or ananalog or prodrug thereof. In embodiments, the compound is not FNL-0004or an analog or prodrug thereof. In embodiments, the compound is notFNL-0005 or an analog or prodrug thereof. In embodiments, the compoundis not FNL-0009 or an analog or prodrug thereof. In embodiments, thecompound is not FNL-0001 or an analog or prodrug thereof. Inembodiments, the compound is not FNL-0013 or an analog or prodrugthereof. In embodiments, the compound is not FNL-00014 or an analog orprodrug thereof. In embodiments, the compound is not FNL-0015 or ananalog or prodrug thereof. In embodiments, the compound is not FNL-0024or an analog or prodrug thereof. In embodiments, the compound is notFNL-0026 or an analog or prodrug thereof. In embodiments, the compoundis not FNL-0016 or an analog or prodrug thereof. In embodiments, thecompound is not FNL-0010 or an analog or prodrug thereof. Inembodiments, the compound is not FNL-0012 or an analog or prodrugthereof. In embodiments, the compound is not FNL-0030 or an analog orprodrug thereof. In embodiments, the compound is not FNL-0036 or ananalog or prodrug thereof. In embodiments, the compound is not FNL-0037or an analog or prodrug thereof. In embodiments, the compound is notFNL-0038 or an analog or prodrug thereof.

In embodiments, the compound is not SMDC 917105. In embodiments, thecompound is not SMDC 917102. In embodiments, the compound is not SMDC916899. In embodiments, the compound is not SMDC 917181. In embodiments,the compound is not SMDC 916860. In embodiments, the compound is notSMDC 916860. In embodiments, the compound is not SMDC 966906. Inembodiments, the compound is not SMDC 917138. In embodiments, thecompound is not SMDC 960055. In embodiments, the compound is not SMDC966921. In embodiments, the compound is not SMDC 966976. In embodiments,the compound is not SMDC 917632. In embodiments, the compound is notSMDC917192. In embodiments, the compound is not SMDC 966938. Inembodiments, the compound is not SMDC 957780. In embodiments, thecompound is not SMDC 966844. In embodiments, the compound is not SMDC966854. In embodiments, the compound is not SMDC 966782. In embodiments,the compound is not SMDC 966849. In embodiments, the compound is notSMDC 966859. In embodiments, the compound is not SMDC 966539. Inembodiments, the compound is not SMDC 966781. In embodiments, thecompound is not SMDC 966846. In embodiments, the compound is not SMDC957828. In embodiments, the compound is not SMDC 966783. In embodiments,the compound is not SMDC966536. In embodiments, the compound is not SMDC966541. In embodiments, the compound is not SMDC 966794. In embodiments,the compound is not SMDC 966793. In embodiments, the compound is notSMDC 966785. In embodiments, the compound is not SMDC 966538. Inembodiments, the compound is not SMDC 966858. In embodiments, thecompound is not SMDC 966857. In embodiments, the compound is not SMDC966789. In embodiments, the compound is not SMDC 957835. In embodiments,the compound is not SMDC 957827. In embodiments, the compound is notSMDC 966844. In embodiments, the compound is not SMDC 916860. Inembodiments, the compound is not SMDC 917162. In embodiments, thecompound is not SMDC 966849. In embodiments, the compound is not SMDC917105. In embodiments, the compound is not SMDC 916929. In embodiments,the compound is not SMDC 996794. In embodiments, the compound is notSMDC 917181. In embodiments, the compound is not SMDC 966854. Inembodiments, the compound is not SMDC 966976. In embodiments, thecompound is not SMDC 957805. In embodiments, the compound is not SMDC957833. In embodiments, the compound is not SMDC 916960.

In embodiments, the compound is not SMDC 917105 or an analog or prodrugthereof. In embodiments, the compound is not SMDC 917102 or an analog orprodrug thereof. In embodiments, the compound is not SMDC 916899 or ananalog or prodrug thereof. In embodiments, the compound is not SMDC917181 or an analog or prodrug thereof. In embodiments, the compound isnot SMDC 916860 or an analog or prodrug thereof. In embodiments, thecompound is not SMDC 916860 or an analog or prodrug thereof. Inembodiments, the compound is not SMDC 966906 or an analog or prodrugthereof. In embodiments, the compound is not SMDC 917138 or an analog orprodrug thereof. In embodiments, the compound is not SMDC 960055 or ananalog or prodrug thereof. In embodiments, the compound is not SMDC966921 or an analog or prodrug thereof. In embodiments, the compound isnot SMDC 966976 or an analog or prodrug thereof. In embodiments, thecompound is not SMDC 917632 or an analog or prodrug thereof. Inembodiments, the compound is not SMDC917192 or an analog or prodrugthereof. In embodiments, the compound is not SMDC 966938 or an analog orprodrug thereof. In embodiments, the compound is not SMDC 957780 or ananalog or prodrug thereof. In embodiments, the compound is not SMDC966844 or an analog or prodrug thereof. In embodiments, the compound isnot SMDC 966854 or an analog or prodrug thereof. In embodiments, thecompound is not SMDC 966782 or an analog or prodrug thereof. Inembodiments, the compound is not SMDC 966849 or an analog or prodrugthereof. In embodiments, the compound is not SMDC 966859 or an analog orprodrug thereof. In embodiments, the compound is not SMDC 966539 or ananalog or prodrug thereof. In embodiments, the compound is not SMDC966781 or an analog or prodrug thereof. In embodiments, the compound isnot SMDC 966846 or an analog or prodrug thereof. In embodiments, thecompound is not SMDC 957828 or an analog or prodrug thereof. Inembodiments, the compound is not SMDC 966783 or an analog or prodrugthereof. In embodiments, the compound is not SMDC 966536 or an analog orprodrug thereof. In embodiments, the compound is not SMDC 966541 or ananalog or prodrug thereof. In embodiments, the compound is not SMDC966794 or an analog or prodrug thereof. In embodiments, the compound isnot SMDC 966793 or an analog or prodrug thereof. In embodiments, thecompound is not SMDC 966785 or an analog or prodrug thereof. Inembodiments, the compound is not SMDC 966538 or an analog or prodrugthereof. In embodiments, the compound is not SMDC 966858 or an analog orprodrug thereof. In embodiments, the compound is not SMDC 966857 or ananalog or prodrug thereof. In embodiments, the compound is not SMDC966789 or an analog or prodrug thereof. In embodiments, the compound isnot SMDC 957835 or an analog or prodrug thereof. In embodiments, thecompound is not SMDC 957827 or an analog or prodrug thereof. Inembodiments, the compound is not SMDC 966844 or an analog or prodrugthereof. In embodiments, the compound is not SMDC 916860 or an analog orprodrug thereof. In embodiments, the compound is not SMDC 917162 or ananalog or prodrug thereof. In embodiments, the compound is not SMDC966849 or an analog or prodrug thereof. In embodiments, the compound isnot SMDC 917105 or an analog or prodrug thereof. In embodiments, thecompound is not SMDC 916929 or an analog or prodrug thereof. Inembodiments, the compound is not SMDC 996794 or an analog or prodrugthereof. In embodiments, the compound is not SMDC 917181 or an analog orprodrug thereof. In embodiments, the compound is not SMDC 966854 or ananalog or prodrug thereof. In embodiments, the compound is not SMDC966976 or an analog or prodrug thereof. In embodiments, the compound isnot SMDC 957805 or an analog or prodrug thereof. In embodiments, thecompound is not SMDC 957833 or an analog or prodrug thereof. Inembodiments, the compound is not SMDC 916960 or an analog or prodrugthereof.

III. PHARMACEUTICAL COMPOSITIONS

In an aspect is provided a pharmaceutical composition including acompound described herein and a pharmaceutically acceptable excipient.

In embodiments, the pharmaceutical composition includes an effectiveamount of the compound. In embodiments, the pharmaceutical compositionincludes a therapeutically effective amount of the compound. Inembodiments, the pharmaceutical composition includes a second agent(e.g., an anti-cancer agent). In embodiments of the pharmaceuticalcompositions, the pharmaceutical composition includes a second agent ina therapeutically effective amount. In embodiments, the anti-canceragent is an EGFR inhibitor (e.g. gefitinib (Iressa™), erlotinib(Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab(Vectibix™), vandetanib (Caprelsa™), afatinib/BIBW2992,CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST-1306,ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethylerlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002,WZ3146, AG-490, XL647, PD153035, or BMS-599626). In embodiments, theanti-cancer agent is erlotinib. In embodiments, the anti-cancer agent isgefitinib. In embodiments, the anti-cancer agent is lapatinib. Inembodiments, the anti-cancer agent is panitumumab.

The pharmaceutical compositions may include optical isomers,diastereomers, or pharmaceutically acceptable salts of the modulatorsdisclosed herein. The compound included in the pharmaceuticalcomposition may be covalently attached to a carrier moiety.Alternatively, the compound included in the pharmaceutical compositionis not covalently linked to a carrier moiety.

IV. METHODS FOR TREATING CANCER

In another aspect, is provided a method of treating cancer in a subjectin need of such treatment (patient). The method including administeringa therapeutically effective amount of a compound described herein(including embodiments, examples, figures, tables) to the subject. Insome embodiments, the cancer is lung cancer, colorectal cancer, coloncancer, pancreatic cancer, breast cancer, or leukemia. In someembodiments, the cancer is lung cancer. In some embodiments, the canceris non-small cell lung cancer. In some embodiments, the cancer is coloncancer. In some embodiments, the cancer is colorectal cancer. In someembodiments, the cancer is breast cancer. In some embodiments, thecancer is leukemia. In some embodiments, the cancer is pancreaticcancer. In some embodments, the cancer is a cancer associated withaberrant K-Ras. In some embodiments, the cancer is a cancer associatedwith a mutant K-Ras. In some embodiments, the cancer is a cancerassociated with K-Ras G12C. In some embodiments, the cancer is a cancerassociated with K-Ras G12D. In some embodiments, the cancer is a cancerassociated with K-Ras G12V. In some embodiments, the cancer is a cancerassociated with K-Ras G12S. In some embodiments, the cancer is a cancerassociated with K-Ras G13C. In some embodiments, the cancer is a cancerassociated with K-Ras G13D. In embodiments, the treating does notinclude preventing.

The compounds of the invention (i.e. compounds described herein,including in embodiments, examples, figures, tables) can be administeredalone or can be coadministered to the patient. Coadministration is meantto include simultaneous or sequential administration of the compoundsindividually or in combination (more than one compound). Thus, thepreparations can also be combined, when desired, with other activesubstances (e.g. to reduce metabolic degradation or anti-cancer agents).In embodiments, the anti-cancer agent is an EGFR inhibitor (e.g.gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™),lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™),afatinib/BIBW2992, CI-1033/canertinib, neratinib/HKI-272, CP-724714,TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804,OSI-420/desmethyl erlotinib, AZD8931, AEE788, pelitinib/EKB-569,CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, orBMS-599626). In embodiments, the anti-cancer agent is erlotinib. Inembodiments, the anti-cancer agent is gefitinib. In embodiments, theanti-cancer agent is lapatinib. In embodiments, the anti-cancer agent ispanitumumab.

V. METHODS OF MODULATING ACTIVITY

In an aspect is provided a method of reducing the level of activity of aK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) protein, the methodincluding contacting the K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B) protein with a compound described herein (including in embodiments,examples, figures, and tables). In some embodiments, the activity of theK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) protein is it'sGTPase activity, nucleotide exchange, differential GDP or GTP binding,effector protein binding, effector protein activation, guanine exchangefactor (GEF) binding, GEF-facilitated nucleotide exchange, phosphaterelease, nucleotide release, nucleotide binding, K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) subcellular localization, K-Ras (e.g.,human K-Ras 4A and/or human K-Ras 4B) post-translational processing,K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) post-translationalmodifications, prenylation, or a GTP bound K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) signaling pathway. In some embodiments, theactivity of the K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)protein is its GTPase activity, nucleotide exchange, effector proteinbinding, effector protein activation, guanine exchange factor (GEF)binding, GEF-facilitated nucleotide exchange, phosphate release,nucleotide release, nucleotide binding, or the activity of a GTP boundK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) signaling pathway. Insome embodiments, the activity of the K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B) protein is the activity of a signaling pathway activatedby GTP bound K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) (i.e.,the method reduces the activity of the signaling pathway activated byGTP bound K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B). In someembodiments, the modulating is increasing the activity of the K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) protein. In someembodiments, the modulating is reducing the activity of the K-Ras (e.g.,human K-Ras 4A and/or human K-Ras 4B) protein. In some embodiments, theK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) protein is a humanK-Ras protein. In some embodiments, the human K-Ras protein includes aG12C mutation. In some embodiments, the human K-Ras protein includes aG12V mutation. In some embodiments, the human K-Ras protein includes aG12S mutation. In some embodiments, the human K-Ras protein includes aG12D mutation. In some embodiments, the human K-Ras protein includes aG13C mutation. In some embodiments, the human K-Ras protein includes aG13D mutation. In some embodiments, the K-Ras protein is a human K-Ras4Aprotein. In some embodiments, the K-Ras protein is a human K-Ras4Bprotein. In some embodiments, the K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B) protein is a mutant K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B) protein. In some embodiments, the K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) protein is an activated K-Ras (e.g.,human K-Ras 4A and/or human K-Ras 4B) protein. In some embodiments, theK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) protein is within abiological cell (e.g., a cancer cell). In some embodiments, thebiological cell forms part of an organism. In some embodiments of themethod of modulating the activity of a K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) protein including contacting the K-Ras (e.g.,human K-Ras 4A and/or human K-Ras 4B) protein with an effective amountof a compound described herein (including in embodiments, examples,figures, and tables), the compound is less effective at modulating theactivity of an H-Ras protein (e.g., compared to the level of modulationof K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)). In someembodiments of the method, the compound modulates the activity of K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) at least two-fold more thanit modulates the activity of H-Ras. In some embodiments of the method,the compound modulates the activity of K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) at least five-fold more than it modulates theactivity of H-Ras. In some embodiments of the method, the compoundmodulates the activity of K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B) at least ten-fold more than it modulates the activity of H-Ras. Insome embodiments of the method, the compound modulates the activity ofK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) at least fifty-foldmore than it modulates the activity of H-Ras. In some embodiments of themethod of modulating the activity of a K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) protein including contacting the K-Ras (e.g.,human K-Ras 4A and/or human K-Ras 4B) protein with an effective amountof a compound described herein (including embodiments, examples,figures, and tables), the compound is less effective at modulating theactivity of an N-Ras protein. In some embodiments of the method, thecompound modulates the activity of K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B) at least two-fold more than it modulates the activity ofN-Ras. In some embodiments of the method, the compound modulates theactivity of K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) at leastfive-fold more than it modulates the activity of N-Ras. In someembodiments of the method, the compound modulates the activity of K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) at least ten-fold more thanit modulates the activity of N-Ras. In some embodiments of the method,the compound modulates the activity of K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) at least fifty-fold more than it modulates theactivity of N-Ras. In embodiments, the compound contacts the K-Ras aminoacid corresponding to H95 of human K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B). In embodiments, compound covalently binds the K-Rasamino acid corresponding to H95 of human K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B). In embodiments, the compound contacts H95 ofhuman K-Ras 4A. In embodiments, the compound contacts H95 of human K-Ras4B. In embodiments, the compound contacts H95 of both human K-Ras 4A andhuman K-Ras 4B. In embodiments, the compound inhibits the activity ofhuman K-Ras 4A. In embodiments, the compound inhibits the activity ofhuman K-Ras 4B. In embodiments, the compound inhibits the activity ofboth human K-Ras 4A and human K-Ras 4B. In embodiments, the compound iscapable of inhibiting the activity of human K-Ras 4A. In embodiments,the compound is capable of inhibiting the activity of human K-Ras 4B. Inembodiments, the compound is capable of inhibiting the activity of bothhuman K-Ras 4A and human K-Ras 4B. In embodiments, the compound inhibitsK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) binding to a secondprotein. In embodiments, the compound inhibits K-Ras (e.g., human K-Ras4A and/or human K-Ras 4B) binding to a second protein and does notinhibit K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) GTPaseactivity (e.g., intrinsic GTPase activity). In embodiments, the compoundinhibits K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) downstreampathway activity activated by GTP bound K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B). In embodiments, the compound inhibits K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) downstream pathway activityactivated by GTP bound K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B) and does not inhibit K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B) GTPase activity (e.g., intrinsic GTPase activity). In embodiments,the compound reduces GTP bound K-Ras (e.g., human K-Ras 4A and/or humanK-Ras 4B) contact with a protein (e.g., effector or downstream componentof pathway) and does not inhibit K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B) GTPase activity (e.g., intrinsic GTPase activity).

In another aspect, a method of modulating a K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) protein is provided. The method includingcontacting the K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)protein with an effective amount of a compound described herein(including in embodiments, examples, figures, and tables). In someembodiments, the K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)protein is modulated (e.g., inhibited relative to absence of thecompound) in K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)subcellular localization, K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B) post-translational processing, K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B) post-translational modifications, or a GTP bound K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) signaling pathway. In someembodiments, the modulating is increasing the post-translationalprocessing or modifications of the K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B) protein. In some embodiments, the modulating is reducingthe post-translational processing or modifications of the K-Ras (e.g.,human K-Ras 4A and/or human K-Ras 4B) protein. In some embodiments, theK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) protein is a humanK-Ras protein. In some embodiments, the human K-Ras protein contains aG12C mutation. In some embodiments, the human K-Ras protein contains aG12V mutation. In some embodiments, the human K-Ras protein contains aG12S mutation. In some embodiments, the human K-Ras protein contains aG12D mutation. In some embodiments, the human K-Ras protein contains aG13C mutation. In some embodiments, the human K-Ras protein contains aG13D mutation. In some embodiments, the K-Ras protein is a human K-Ras4Aprotein. In some embodiments, the K-Ras protein is a human K-Ras4Bprotein. In some embodiments, the K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B) protein is a mutant K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B) protein. In some embodiments, the K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) protein is an activated K-Ras protein.In some embodiments, the K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B) protein is within a biological cell. In some embodiments, thebiological cell forms part of an organism. In embodiments, compound(e.g., compound described herein) modulates the stability of the K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) protein. In embodiments,compound (e.g., compound described herein) reduces the stability of theK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) protein relative tothe absence of the compound. In embodiments, compound (e.g., compounddescribed herein) increases the rate of degradation of the K-Ras (e.g.,human K-Ras 4A and/or human K-Ras 4B) protein relative to the absence ofthe compound.

In embodiments, the compound (e.g., compound described herein) contactsthe amino acid corresponding to His95 in K-Ras (e.g., human K-Ras 4A(SEQ ID NO:4) and/or human K-Ras 4B (SEQ ID NO:5). In embodiments, thecompound (e.g., compound described herein) reacts with His95 in K-Ras(e.g., human K-Ras 4A (SEQ ID NO:4) and/or human K-Ras 4B (SEQ ID NO:5).In embodiments, the compound (e.g., compound described herein)covalently binds to the amino acid corresponding to His95 in K-Ras(e.g., human K-Ras 4A (SEQ ID NO:4) and/or human K-Ras 4B (SEQ ID NO:5).In embodiments, the compound (e.g., compound described herein)covalently reacts with His95 in K-Ras (e.g., human K-Ras 4A (SEQ IDNO:4) and/or human K-Ras 4B (SEQ ID NO:5). In embodiments, the compound(e.g., compound described herein) is capable of binding to the aminoacid corresponding to His95 of K-Ras (e.g., human K-Ras 4A (SEQ ID NO:4)and/or human K-Ras 4B (SEQ ID NO:5). In embodiments, the compound (e.g.,compound described herein) is capable of reacting with His95 of K-Ras(e.g., human K-Ras 4A (SEQ ID NO:4) and/or human K-Ras 4B (SEQ ID NO:5).

In embodiments, the compound (e.g., compound described herein) binds tothe amino acid corresponding to His95 in K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) protein when the K-Ras (e.g., human K-Ras 4A (SEQID NO:4) and/or human K-Ras 4B (SEQ ID NO:5) protein Cys185 (or aminoacid corresponding to Cys185 of K-Ras 4B, SEQ ID NO:5) is covalentlymodified (e.g., prenylated, farnesylated). In embodiments, the compound(e.g., compound described herein) binds to the amino acid correspondingto H95 in K-Ras (e.g., human K-Ras 4A (SEQ ID NO:4) and/or human K-Ras4B (SEQ ID NO:5) protein following protein synthesis, when the K-Ras(e.g., human K-Ras 4A (SEQ ID NO:4) and/or human K-Ras 4B (SEQ ID NO:5)protein Cys185 (or amino acid corresponding to Cys185 of K-Ras 4B SEQ IDNO:5) has not yet been covalently modified (e.g., prenylated,farnesylated).

In embodiments, the compound prevents productive folding of K-Ras (e.g.,human K-Ras 4A and/or human K-Ras 4B) protein (e.g., by binding to K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) protein, by contacting theamino acid corresponding to His95 of K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B)) relative to the absence of the compound. Inembodiments, the compound increases misfolding of K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) protein (e.g., by binding to K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) protein, by contacting theamino acid corresponding to His95 of K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B)) relative to the absence of the compound. Inembodiments, the compound increases unfolding of K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) protein (e.g., by binding to K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) protein, by contacting theamino acid corresponding to His95 of K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B)) relative to the absence of the compound. Inembodiments, the compound increases degradation of K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) protein (e.g., by binding to K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) protein, by contacting theamino acid corresponding to His95 of K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B)) relative to the absence of the compound. Inembodiments, the compound reduces GTP binding to K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) protein (e.g., by binding to K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) protein, by contacting theamino acid corresponding to His95 of K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B)) relative to the absence of the compound. Inembodiments, the compound decreases GDP release by K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) protein (e.g., by binding to K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) protein, by contacting theamino acid corresponding to His95 of K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B)) relative to the absence of the compound. Inembodiments, the compound decreases interactions of a second protein(e.g., pathway component, effector) with K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) protein (e.g., by binding to K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) protein, by contacting the amino acidcorresponding to His95 of K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B)) relative to the absence of the compound. In embodiments, thecompound decreases prenylation (e.g., farnesylation,geranylgeranylation) of K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B) protein (e.g., by binding to K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B) protein, by contacting the amino acid corresponding toHis95 of K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)) relative tothe absence of the compound. In embodiments, the compound decreasesdegradation of K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)protein (e.g., by binding to K-Ras (e.g., human K-Ras 4A and/or humanK-Ras 4B) protein, by contacting the amino acid corresponding to His95of K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)) relative to theabsence of the compound. In embodiments, the compound stabilizes theconformation of K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)protein (e.g., by binding to K-Ras (e.g., human K-Ras 4A and/or humanK-Ras 4B) protein, by contacting the amino acid corresponding to His95of K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)) relative to theabsence of the compound. In embodiments, the compound stabilizes aconformation of K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)protein (e.g., by binding to K-Ras (e.g., human K-Ras 4A and/or humanK-Ras 4B) protein, by contacting the amino acid corresponding to His95of K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)) relative to theabsence of the compound. In embodiments, the compound reduces proteinflexibility of K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)protein (e.g., by binding to K-Ras (e.g., human K-Ras 4A and/or humanK-Ras 4B) protein, by contacting the amino acid corresponding to His95of K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)) relative to theabsence of the compound.

In embodiments, the compound decreases (e.g., by at least 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96,97, 98, or 99%) the level of K-Ras (e.g., human K-Ras 4A and/or humanK-Ras 4B) function in a cell (e.g., by binding to K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) protein, by contacting the amino acidcorresponding to His95 of K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B)) relative to the absence of the compound, in less than about 1 hour(e.g., less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, or 50minutes). In embodiments, the compound decreases (e.g., by at least 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 91, 92, 93,94, 95, 96, 97, 98, or 99%) the level of K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) function in a cell (e.g., by binding to K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) protein, by contacting theamino acid corresponding to His95 of K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B)) relative to the absence of the compound, in less than 1hour (e.g., less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, or 50minutes). In embodiments, the compound decreases (e.g., by at least 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 91, 92, 93,94, 95, 96, 97, 98, or 99%) the level of K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) function in a cell (e.g., by binding to K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) protein, by contacting theamino acid corresponding to His95 of K-Ras (e.g., human K-Ras 4A and/orhuman K-Ras 4B)) relative to the absence of the compound, in less thanabout 1 day (e.g., less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 hours). Inembodiments, the compound decreases (e.g., by at least 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97,98, or 99%) the level of K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B) function in a cell (e.g., by binding to K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) protein, by contacting the amino acidcorresponding to His95 of K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B)) relative to the absence of the compound, in less than 1 day (e.g.,less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, or 23 hours). In embodiments, the compound decreases(e.g., by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60,70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) the level of K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B) function in a cell (e.g.,by binding to K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)protein, by contacting the amino acid corresponding to His95 of K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B)) relative to the absence ofthe compound, in less than about 1 month (e.g., less than about 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, or 30 days). In embodiments, the compounddecreases (e.g., by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40,50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) the level ofK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) function in a cell(e.g., by binding to K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)protein, by contacting the amino acid corresponding to His95 of K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B)) relative to the absence ofthe compound, in less than 1 month (e.g., less than 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, or 30 days). In embodiments, the compound binds to K-Ras(e.g., only K-Ras 4B, only K-Ras 4A, or both K-Ras 4A and K-Ras 4B). Inembodiments, the compound decreases (e.g., by at least 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97,98, or 99%) the level of K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B) function in a cell (e.g., by binding to K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) protein, by contacting the amino acidcorresponding to His95 of K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B)) relative to the absence of the compound, in less than 48 hours(e.g., less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 hours). Inembodiments, the compound decreases (e.g., by at least 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97,98, or 99%) the level of K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B) protein in a cell (e.g., by binding to K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) protein, by contacting the amino acidcorresponding to His95 of K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B)) relative to the absence of the compound, in less than 48 hours(e.g., less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 hours). Inembodiments, the compound decreases (e.g., by at least 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97,98, or 99%) the level of K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B) function in a cell (e.g., by binding to K-Ras (e.g., human K-Ras 4Aand/or human K-Ras 4B) protein, by contacting the amino acidcorresponding to His95 of K-Ras (e.g., human K-Ras 4A and/or human K-Ras4B)) relative to the absence of the compound, in less than 72 hours(e.g., less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,71, or 72 hours). In embodiments, the compound decreases (e.g., by atleast 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 91,92, 93, 94, 95, 96, 97, 98, or 99%) the level of K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B) protein in a cell (e.g., by binding toK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) protein, bycontacting the amino acid corresponding to His95 of K-Ras (e.g., humanK-Ras 4A and/or human K-Ras 4B)) relative to the absence of thecompound, in less than 72 hours (e.g., less than 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, or 72 hours). In embodiments, thecompound decreases (e.g., by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20,30, 40, 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) thelevel of K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) function ina cell (e.g., by binding to K-Ras (e.g., human K-Ras 4A and/or humanK-Ras 4B) protein, by contacting the amino acid corresponding to His95of K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)) relative to theabsence of the compound, in less than 100 hours (e.g., less than 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99, or 100 hours). In embodiments, the compounddecreases (e.g., by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40,50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%) the level ofK-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B) protein in a cell(e.g., by binding to K-Ras (e.g., human K-Ras 4A and/or human K-Ras 4B)protein, by contacting the amino acid corresponding to His95 of K-Ras(e.g., human K-Ras 4A and/or human K-Ras 4B)) relative to the absence ofthe compound, in less than 100 hours (e.g., less than 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,98, 99, or 100 hours).

VI. EXAMPLES

The development of small-molecule inhibitors that directly target Ras ishighly desirable, but has proven to be a major challenge. All isoformsof the Ras protein (HRas, NRas and KRas) play essential roles in normalcells. Therefore, one desirable Ras-targeting drug would specificallytarget the oncogenic form of the protein. However, targeting K-Ras(without distinguishing between wildtype and mutant protein) could be aneffective approach, since all isoforms are redundant in normal tissues,and eliminating one is expected to be tolerable.

Recently, we discovered that histidine 95 (H95) in KRas—a residue thatwas not previously considered as a potential drug target in KRas, couldbe covalently modified by electrophiles. The importance of thisdiscovery is that H95 is unique for KRas, (Q in HRas and L in NRas, FIG.1). This creates the opportunity for direct drug-targeting of thisunique site. Moreover, targeting H95 as it is in a G-domain, wouldaffect both Kras4A and 4B splice variants of KRas. The covalently (e.g.,irreversibly) modified KRas protein could be sent for degradation,or—since H95 resides in helix 3 near switch II—this modification couldimpair effector(s) binding. We have since utilized H95C mutant proteinand disulfide tethering to find small molecule fragments that bind atthis location. These studies led to the discovery of two hit-series withdemonstrable SAR: triazoles and phenylacetamides. Through an iterativeapproach we followed up functionalizing selected hits with irreversibleelectrophilic groups. One of these irreversible electrophiles—a triazolewith an epoxide moiety, growth arrested KRas-driven mouse embryonicfibroblasts (MEFs), but not BRAF-driven MEFs. This compound (FNL-0012)covalently modified H95C KRas protein; however, caused minimalmodification to C185 in KRas WT protein, and did not modify FMe-KRasprotein in vitro. In cell culture, this compound caused growth arrestwithin 24 h and a decrease in MEK phosphorylation 1 h after treatmentwas initiated, both in KRas MEFs and in pancreatic cancer cell lines,and not in BRAF MEFs. This compound may function through noncovalentbinding to KRas protein. To investigate the role of the epoxide oxygen acyclopropyl control compound was prepared. This analogue did not causegrowth arrest or any perturbations in MAPK signaling. FNL-0012 may bindKRas non-covalently by virtue of a H-bonding interaction between theepoxide oxygen and the H95 sidechain. FNL-0012 may bind in a pocketnearby H95, influencing Switch2/effector(s) binding to KRas.

Example 1. Tethering Screen

Disulfide tethering is a site-directed fragment-based approach todrug-discovery, which allows the screening low-affinity disulfidecontaining fragments against a native or introduced cysteine residue ofa target protein. Fragment binding is reversible, and can be tuned tofavor detection of only the strongest bound fragments through the use ofincreasing concentrations of a reductant (typically β-mecaptoethanol).This binding is not purely driven by reactivity; it is influenced byprotein/ligand interactions and is independent of pKa or surfaceexposure. Bound fragments are detected by mass spectrometry and providea lead into the drug discovery process.

To target H95 specifically, we generated Kras4b H95C (1-169) mutantprotein, and used it (GppNHp-loaded), to search for compounds that couldbind to active KRas in close proximity to H95. We performed a tetheringscreen of a disulfide containing fragment library at the University ofCalifornia San Francisco. The initial screen consisted of >1600fragments and resulted in a number of hits. We selected 52 compoundsrepresentative of this data-set for further evaluation in a doseresponse screen.

Example 2. Compounds Including Phenylacetamide

Example 3. Compounds Including Triazole

Example 4. Additional Binding Compounds

Example 5. Modification of Disulfide Moieties to AlternativeElectrophilic Moieties

Chemistry efforts focused upon functionalizing selected hits withelectrophilic (e.g., irreversible) moieties (FIG. 5). These covalentcompounds were initially screened for K-Ras binding affinity using massspectrometry/biophysical/biochemical methods, which were followed upwith cell-based experiments. We modified 966844, 966854, and 917105 witha tetrafluorophenoxymethyl ketone electrophilic moiety to generatecovalent analogues of the original hits (FIG. 5), then investigatedsubstitutions of the linker group (FIG. 5), and the introduction ofalternative electrophiles (FIG. 5).

Example 6. Biological Characterization

We used mouse embryo fibroblasts (MEFs) that have been rescued by KRas4bG12D or BRAF V600E that are essential for proliferation of these cells(Drosten et al. EMBO Journal, 2010). Inhibition of KRas/MAPK pathway inthese cells results in growth arrest, making these KRas- or BRAF-drivenMEFs a useful tool in Ras-drug discovery.

Compound FNL-0012 (epoxide derivative of 966844) showed dose-dependentgrowth arrest in KRAS4b G12D MEFs, without signs of toxicity, suggestinga direct inhibitory effect on KRAS. Growth arrest was observed within 24h after treatment was initiated (FIG. 8A), and was very clearlydose-dependent after 45 h, without toxicity up to 50 μM (FIG. 8C).Decrease in KRas level was seen after 45 h of treatment, but not within24 h.

Next, we treated pancreas carcinoma cells HupT4 with FNL-0012, andFNL-0010—an epoxide derivative of fragment 917105, for 24 h. FNL-0012growth arrested these cells within 24 h, a weaker binder (based ontethering screen dose-response data) FNL-0010 did not affect cellproliferation in this assay (FIG. 8F). Analysis of MAPK signaling inHupT4 revealed downregulation of P-MEK, and to lesser extend P-Erk after24 h treatment with FNL-0012, but not with FNL-0010 in this assay (FIG.7E).

Example 7. Covalent Modification of K-Ras

Both FNL-0012 and FNL-0010 did not label fully processed (farnesylatedand carboxymethylated KRas(FMe-KRas) (MALDI-TOF analysis), and whenreacted with full length 1-188 KRas protein minimal modification to C185with FNL-0012 was observed after 24 h (FIG. 9). This level ofmodification is too small to justify the degree of growth arrestobserved in MEFs within 24 h of treatment with this compound.

Next, we reacted all three epoxides synthesized (structures depicted inFIG. 10A) with KRas H95C (1-169) to investigate reactivity at that site.All three compounds covalently labeled C95, but level of modification tothis cysteine by derivatives of two strong binding fragments from thetethering screen (FNL-0012 and -0030) was significantly higher (FIG.10B) than that of the weaker binder FNL-0010.

Example 8. Further Biological Characterization

Derivatives of FNL-0012 shown in FIG. 11A were synthesized to be used ascontrols in biochemical and cell-based experiments: tetrahydrofuran(FNL-0036), cyclopropyl (FNL-0037), and oxetane (FNL-0038). HupT4pancreas carcinoma cells treated with FNL-0012 or the above controlcompounds responded with growth arrest to FNL-0012 only (FIG. 11B).There was a decrease in MAPK signaling with FNL-0012 only at 24 h, andin KRas protein and MAPK signaling after 72 h (FIG. 11C).

Example 9. Biological Characterization in BRAF V600E, Ras IndependentCells

We investigated effects of FNL-0012 in BRAF V600E-driven MEFs that areRas-independent. FNL-0012 did not cause growth arrest in BRAF V600EMEFs, nor decrease in MEK phosphorylation (FIG. 12A-12B).

Example 10. Ongoing Compound Derivatization

We are investigating alternative electrophiles and developing ahistidine-specific warhead. For this purpose, we generated MEF celllines expressing Kras H95Q. We will use these two pairs of Kras MEFs:G12D vs G12D/H95Q, and WT vs WT/H95Q to investigate compounds'effectiveness against K-ras, and H95-binding specificity.

Fumagillin-like spiroepoxytriazoles irreversibly inhibit methinonineaminopeptidate 2 (MetAP2) with potent cellular activity through covalentmodification of His231 (Morgen et al. 2016 (DOI:10.1021/acschembio.5b00755), incorporated herein by reference for allpurposes). Ongoing efforts are incorporating similar electrophiles intocompounds described herein, which specifically target Kras H95.

To further investigate the role of the epoxide group in K-Ras inhibitionwe are synthesizing a number of analogues of FNL-0010, -0012, and -0030.Initially, we are exploring the effect of steric hindrance on epoxidebinding. We are also examining a number of heterocyclic compounds withan aim of mimicking the proposed H-bond interaction of the epoxideoxygen with H95. Finally, we are investigating alternative electrophilicgroups for covalent modification of H95.

A) Epoxide Analogues

B) Alternative Heterocycles

C) Alternative Electrophiles

We are investigating derivatives of compound FNL-0030.

Example 11: Further In Vitro Characterization

In an experiment similar to Example 6, a HupT4 pancreas cancer cell lineharboring KRAS G12V mutation and considered RAS-dependent showed growtharrest and dose-dependent decrease in KRAS level and MAPK signalingassociated with treatment with FNL-0012 (FIG. 13).

Example 12: Characterization of Selected Enantiomers

Single enantiomers of FNL-0012, compounds FNL-004.2 (5) and FNL-0044(R), then corresponding single enantiomers of FNL-0030, compoundsFNL-0043 (S) and FNL-0045 (R), were synthesized (FIG. 14A). Theseenantiomers were investigated using a MALDI-TOF MS screen using KRAS4b(1-169) H95C, and also cell-based assays. The level of covalentmodification to KRAS4b H95C was significantly higher in the (R)enantiomer compared to the (S) counterpart (FIG. 14B). This alsotranslated to antiproliferative activity of (R) isomers, with (S) beinginactive (FIG. 14C).

Example 13: Analogues of FNL-0045

Analogues of compound FNL-0045 (FIG. 15A) were synthesized and assessed.Methyl substitution converting the imidazole to indole increasedstability of the compound and prevented dimer formation. FIG. 15Bdemonstrates that compound FNL-0088 (R enantiomer) compared favorably inthe proliferation assay with the (S) enantiomer, compound FNL-0090.

Example 14: Additional Compounds

Table 1 is a table summarizing levels of covalent labeling to C95 asanalyzed by MALDI-TOF MS for a series of synthesized compounds.Recombinant KRAS4b H95C/C118S protein was used in a GDP-loaded(inactive) form, or nucleotide exchange was performed as described inExperimental Section below. Both species, GDP or nonhydrolyzableanalogue of GTP—GppNHp-loaded KRAS4b H95C/C118S, were then reacted witha panel of epoxides and analyzed by MALDI-TOF MS to assess level ofcovalent modification to C95 after 3 h, 6 h, or 24 h of incubation withthe protein. All R isomers show enhanced activity compared to S isomers.Protein in a GDP state shows higher level of covalent modification thanthe GppNHp-loaded protein.

TABLE 1 GDP GppNHp Compound 3 h 6 h 24 h 3 h 6 h 24 h

0 0 0 0 0 0

3 9 38 0 3 13

0 0 0 0 0 0

7 18 72 2 4 25

0 5 31 0 2 11

23 52 96 0 4 19

5 12 45 2 3 14

3 10 49 0 2 10

36 73 98 0 2 17

19 42 91 3 4 22

87 91 89 76 81 78

0 0 0 0 0 0

0 0 0 0 0 0

0 0 0 0 0 0

Example 15: Cell Proliferation Assays

Cell viability in the presence of compounds (discussed in examplesabove) was measured using CellTiter-Glo (Promega). Cells were plated inblack-walled 384-well plates (Greiner, 781091) at densities inaccordance with their doubling time (for MEFs typically 1,000 cells/wellin 20 μl), using the Multidrop Combi Reagent Dispenser (Thermo). Theywere then incubated overnight at 37° C. in a humidified atmosphere of 5%CO₂ prior to compound addition.

Compound and dimethylsulfoxide (DMSO) addition to microplates wasperformed using the Access Laboratory Workstation (Labcyte) and Echo 555(Labcyte) liquid handler. Source plates with compounds and DMSO wereprepared and the Echo 555 was used to transfer 50 nL of compound, DMSO,or both to the appropriate wells. Five L of complete culture medium wasadded to all wells of the microplate after compound addition. Thehighest final concentration in each assay was 100 μM or 50 μM withbetween seven to 12 dilutions. The final DMSO concentration in all wellswas 0.2%.

Cells were incubated with compounds for 72 h. All conditions were donein triplicates and experiments performed at least thrice. Cellular ATPlevels (an indicator of cell count) were determined with CellTiter-Glo(CTG, Promega G7573) luminescence assay, using an EnVision Plate Reader(PerkinElmer).

Plates were harvested at two time points. At the time of drug addition,one plate for each cell line with no compounds added received 5 μL ofmedia and were harvested to represent a measurement of the cellpopulation at the time of compound addition (T0). After 72 h incubation,the compound treated plates were harvested using CTG reagent andluminescence read using the EnVision giving control growth (C) andcompound treated well (T72) measurements. Growth inhibition wascalculated by:

$\frac{{T\; 72} - {T\; 0}}{C - {T\; 0}} \times 100$Dose-response curves were generated using Prism 7 software (GraphPad).

Example 16: Immunoblot Analysis

For immunoblot analysis experiments, cells rinsed trice with ice-coldphosphate-buffered saline (PBS) were lysed on ice, with ice-cold TNEbuffer, supplemented with Halt protease and phosphatase inhibitors(Thermo Scientific), and centrifuged at 15,000 g for 15 minutes tocollect whole-cell lysates. Protein concentration was measured with theBCA protein assay (Pierce). Thirty micrograms of total protein persample were loaded into 4%-12% NuPAGE Bis-Tris gradient gels (LifeTechnologies) and separated by SDS-PAGE. Proteins were transferred topolyvinylidene difluoride (PVDF) membranes. The following antibodieswere used for immunoblotting: mouse monoclonal anti-KRAS (SigmaWH0003845M1, clone 3B10-2F2), mouse anti-RAS (Thermo 1862335), rabbitanti-pERK1/2 (T202/Y204; Cell Signaling Technology 4370), mouseanti-ERK1/2 (Cell Signaling Technology 4696), rabbit anti-p-MEK1/2(S217/221; Cell Signaling Technology 9154), mouse anti-MEK1/2 (CellSignaling Technology 4694), rabbit anti-p-AKT (S473; Cell SignalingTechnology 4060), mouse anti-AKT (Cell Signaling Technology 2920).Vinculin (rabbit anti-vinculin, Cell Signaling Technology 4650) was usedas a loading control. Primary antibodies were detected withfluorescence-conjugated (LI-COR) secondary antibodies.

Example 17: GppNHp Nucleotide Exchange Protocol for GDP KRAS Proteins

150 to 300 μM solution of GDP loaded protein in KRAS buffer was prepared(20 mM HEPES, 150 mM NaCl, 1 mM MgCl₂, 0.05 mM TCEP, pH 7.3). To thiswas added vigorously 1500×molar excess of 1 M ammonium sulfate in KRASbuffer, and the combination mixed gently by inverting tube. Next wasprepared 250 mM solution of GppNHp (150 molar excess of GppNHp toprotein; keep it on ice). To the protein was pipetted 10% of preparedGppNHp solution, then suspension of alkaline phosphatase from calfintestine on agarose was added (Sigma-Aldrich, P0726) to have 2 units ofenzyme per each mg of protein. The reaction mixture was incubated atroom temperature, rotating end-over for 1 h 30 min. The alkalinephosphatase was removed on agarose beads by filtering solution to a newvial using Millex-GP syringe filter. Remaining solution of GppNHp wasadded and incubated for additional 45 min. At the end of the exchangethe protein was filtered again, placed on ice, and purified on NGCmedium-pressure chromatography system (Bio-Rad). Five in-lane connecteddesalting columns (5×GE Healthcare HiTrap Desalting columns 5 ml,17-1408-01) were used with isocratic elution of KRAS buffer at 4 ml/min.The protein elution was monitored at 280 nm. The concentration of finalprotein was evaluated by NanoDrop 2000 spectrophotometer (Thermo Fisher)using molar attenuation coefficient ε=19685 l·mol⁻¹·cm⁻¹. The quality ofthe protein was confirmed by MALDI and the exchange rate was assessed byHPLC based assay.

Example 18: Percentage Labeling Determination for Compounds TargetingKRAS4b Residue 95 by Matrix Assisted Laser Desorption Ionization-Time ofFlight Mass Spectrometry (MALDI-TOF)

Proteins:

The assay uses four tool proteins:

-   -   Guanosine diphosphate (GDP) loaded KRAS4b(1-169) H95C/C118S        mutant    -   5′-Guanylyl imidodiphosphate (GppNHp) loaded KRAS4b(1-169)        H95C/C118S mutant    -   GDP loaded KRAS4b(1-169) C118S mutant    -   GppNHp loaded KRAS4b(1-169) C118S mutant

Reaction:

20 μM Solution of protein in 20 mM HEPES, 150 mM NaCl, 1 mM MgCl₂, pH7.3 buffer was prepared freshly before assay. 20 μl Aliquots of proteinwere dispensed on 384 well polypropylene plate, then tested compounds(0.8 μl, 10 mM in DMSO) were added to appropriate wells. For eachreaction/assay three blank and three control samples were prepared bymixing 20 μl of protein solution with 0.8 μl DMSO or 10 mM standards(compounds 994566 and FB9). The wells content was carefully mixed byaspiration, then plate was sealed by adhesive cover, centrifuged at 2000g for 1 minute and kept in dark at room temperature for 3, 6 (or 8) and24 h.

MALDI Target Pre-Treatment:

Before each assay MALDI target (Bruker MPT 384 ground steel BC) waspre-treated by pipetting on each spot 1 μl of saturated sinapinic acidin acetonitrile (ACN). This step significantly improves uniformity ofsample crystallization across the plate resulting in better assaysensitivity.

MALDI Sample Preparation:

After 24 h reaction, 2 μl of reaction mixtures were pipetted out into 20μl MALDI matrix solution (saturated solution of sinapinic acid in 1:1ACN:water solution containing 0.75% trifluoroacetic acid (TFA))deposited on 384 well polypropylene plate. Resulting solution was mixedby aspiration, centrifuged at 2000 g for 1 minute, then 2 μl aliquotswere dispensed on pre-treated MALDI target using Beckman Coulter BiomekFX^(P) 96/Span-8 Laboratory Automation Workstation. Finally, the MALDItarget was dried under mild vacuum to produce spots with finecrystalline structure.

MALDI Measurements:

MALDI-TOF measurements were performed on Bruker Daltonics ultraflex IIITOF-TOF mass spectrometer using linear mode and mass range from 5 to 45kDa. Detector gain was set to ×9 (1734 V), sample rate to 1 GS/s, smartbeam parameter set: 3_medium was used, and the laser frequency was 66.7Hz. Spectra were automatically collected using custom AutoXecute method.Laser power was auto-adjusted using fuzzy control. The peak selectionrange was set to be between 19000 and 20200 Da. Peak evaluation useshalf width parameter set to be smaller than 30 Da. Fuzzy control usedProteins/Oligonucleotides protocol with minimum half width ⅙ times abovethreshold. Up to 1500 shots were collected in 500 shot steps. Dynamictermination was implemented to finish data collection when peakintensity was reaching value of 1200 [a.u.].

Spectra Processing:

Spectra were smoothed by SavitzkyGolay algorithm using 5 m/z width andthree cycles. Centroid peak detection algorithm was used with signal tonoise threshold set to 4, relative intensity threshold 2%, minimumintensity threshold 20 [a.u.], peak width 10 m/z and TopHat baselinesubtraction. Peak intensity and area under the peak were evaluated andrecorded for all peaks between 19248 Da and 20500 Da for H95/C118 mutantand 19285 Da and 20500 Da for C118 mutant respectively.

Calculation:

Percent of labeling was calculated using followed equation:

${\%\mspace{14mu}{modification}} = {\frac{{modified}\mspace{14mu}{protein}\mspace{14mu}{peak}\mspace{14mu}{height}}{\begin{matrix}{{{modified}\mspace{14mu}{protein}\mspace{14mu}{peak}\mspace{14mu}{height}} +} \\{{unmodified}\mspace{14mu}{protein}\mspace{14mu}{peak}\mspace{14mu}{height}}\end{matrix}} \times 100\%}$Similar results were obtained when peak area instead of peak height wasused for calculations, however peak height method produced more reliabledata in case of poor quality spectra.

Tables summarizing protein labeling over time by different compoundsprovided herein are presented in Table 1.

Example 19: Synthesis of 4-Benzene Sulfonyl Triazole Compounds

The compound 1-(oxiran-2-ylmethyl)-4-tosyl-1H-1,2,3-triazole wassynthesized according to the above scheme. Certain compounds comprisinga sulfonyl triazole moiety were synthesized following an analogousroute. In the first step, 2-(chloromethyl)oxirane was combined withNaN₃, acetic acid (AcOH), and water, and the mixture stirred at roomtemperature to produce 1-azido-3-chloropropan-2-ol. This compound wasthen combined with ethynyl p-tolyl sulfone, CuI (0.05%) in dimethylsulfoxide (DMSO) and stirred at room temperature for 18 hours to producea triazole compound. This triazole was combined with NaOH (1N), andacetone, and the mixture stirred at room temperature for 1 h to produce1-(oxiran-2-ylmethyl)-4-tosyl-1H-1,2,3-triazole.

Example 20: Synthesis of 4-Methylamido Triazole Compounds

Certain compounds comprising a 4-methylamido triazole moiety weresynthesized according to the above scheme. In the first step,1-azido-3-chloropropan-2-ol is combined with an R-alkyne reactant,CuSO₄.5H₂O (10%), Na-ascorbate (30%), a mixture of t-butanol and water(tBuOH/water (1:1)), and the mixture stirred at 50° C. for 18 h toproduce a compound comprising a triazole moiety and a3-chloropropan-2-ol moiety. This is then reacted with NaOH (1N) andacetone at room temperature for 1 hour to produce the compoundcomprising a 4-methylamido triazole moiety.

Example 21: Synthesis of Compounds with an Amide Moiety

Certain compounds disclosed herein with an amide moiety, without atriazole moiety, were synthesized according to the above scheme, overtwo steps. In the first step, 1-amino-3-chloropropan-2-ol hydrochloridewas combined with R—COOH, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (EDC.HCl), hydroxybenzotriazole hydrate (HOBt.H₂O),triethylamine (Et₃N), and dichloromethane (DCM), and the mixture stirredat room temperature for 18 h. In the second step, the product from thefirst step was reacted with NaOH (1N) and acetone at room temperaturefor 30 minutes to produce the final compound comprising an amide moiety,without a triazole.

The following compounds were synthesized, for example in some instancesby following synthetic schemes analogous to those shown in Examples19-21 above:

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

Enumerated Embodiments

Embodiment I-1. A compound having the formula:

-   -   wherein,    -   ring A is an aryl or heteroaryl;    -   R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,        —SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B), —NHNR^(1A)R^(1B),        —ONR^(1A)R^(1B), —NHC═(O)NHNR^(1A)R^(1B), —NHC(O)NR^(1A)R^(1B),        —N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C), —C(O)—OR^(1C),        —C(O)NR^(1A)R^(1B), —OR^(1D),        —NR^(1A)SO₂R^(1D)—NR^(1A)C(O)R^(1C), —NR^(1A)C(O)OR^(1C),        —NR^(1A)OR^(1C), —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹, substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, substituted or unsubstituted heteroaryl; two adjacent R¹        substituents may optionally be joined to form a substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   z1 is an integer from 0 to 4;    -   R² is independently hydrogen, —CX² ₃, —CHX² ₂, —CH₂X²,        —C(O)R^(2A), —C(O)OR^(2A), —C(O)NR^(2A)R^(2B), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, substituted or unsubstituted heteroaryl;    -   L¹ is a bond, substituted or unsubstituted alkylene, substituted        or unsubstituted cycloalkylene, or

-   -   L² is a bond, —O—, —C(O)—, —C(O)O—, —OC(O)—, —S—, —SO—, —S(O)₂—,        —NH—, —NHC(O)—, —C(O)NH—, —SO₂NH—, —NHSO₂—, —OC(O)NH—,        —NHC(O)O—, —NHC(O)NH—, —C(O)OCH₂—, —CH₂OC(O)—, —C(O)NHCH₂—,        —CH₂NHC(O)—, —CH₂NHCH₂—, substituted or unsubstituted alkylene,        or substituted or unsubstituted heteroalkylene;    -   L³ is a bond, —S(O)₂—, —N(R³)—, —O—, —S—, —C(O)—, —C(O)N(R³)—,        —N(R³)C(O)—, —N(R³)C(O)NH—, —NHC(O)N(R³)—, —C(O)O—, —OC(O)—,        substituted or unsubstituted alkylene, substituted or        unsubstituted heteroalkylene, substituted or unsubstituted        cycloalkylene, substituted or unsubstituted heterocycloalkylene,        substituted or unsubstituted arylene, or substituted or        unsubstituted heteroarylene;    -   R³ is independently hydrogen, —CX³ ₃, —CHX³ ₂, —CH₂X³,        —C(O)R^(3A), —C(O)OR^(3A), —C(O)NR^(3A)R^(3B), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   L⁴ is a bond, —S(O)₂—, —N(R⁴)—, —O—, —S—, —C(O)—, —C(O)N(R⁴)—,        —N(R⁴)C(O)—, —N(R⁴)C(O)NH—, —NHC(O)N(R⁴)—, —C(O)O—, —OC(O)—,        substituted or unsubstituted alkylene, substituted or        unsubstituted heteroalkylene, substituted or unsubstituted        cycloalkylene, substituted or unsubstituted heterocycloalkylene,        substituted or unsubstituted arylene, or substituted or        unsubstituted heteroarylene;    -   R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴,        —C(O)R^(4A), —C(O)OR^(4A), —C(O)NR^(4A)R^(4B), substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   R⁵ is independently hydrogen, substituted or unsubstituted        alkyl, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, substituted        or unsubstituted heteroaryl, or E;    -   E is a histidine binding moiety;    -   each R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(3A),        R^(3B), R^(4A), and R^(4B) is independently hydrogen, —CX₃, —CN,        —COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; R^(1A) and R^(1B)        substituents bonded to the same nitrogen atom may optionally be        joined to form a substituted or unsubstituted heterocycloalkyl        or substituted or unsubstituted heteroaryl; R^(2A) and R^(2B)        substituents bonded to the same nitrogen atom may optionally be        joined to form a substituted or unsubstituted heterocycloalkyl        or substituted or unsubstituted heteroaryl; R^(3A) and R^(3B)        substituents bonded to the same nitrogen atom may optionally be        joined to form a substituted or unsubstituted heterocycloalkyl        or substituted or unsubstituted heteroaryl; R^(4A) and R^(4B)        substituents bonded to the same nitrogen atom may optionally be        joined to form a substituted or unsubstituted heterocycloalkyl        or substituted or unsubstituted heteroaryl;    -   each X, X¹, X², X³, and X⁴ is independently —F, —Cl, —Br, or —I;    -   n1 is independently an integer from 0 to 4; and    -   m1 and v1 are independently 1 or 2.

Embodiment I-2. The compound of embodiment I-1, having the formula:

Embodiment I-3. The compound of embodiment I-2, wherein

-   -   Ring A is an aryl or heteroaryl;    -   R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,        —SR^(1D), —SO₂R^(1D), —NHC(O)NR^(1A)R^(1B), —N(O)₂,        —NR^(1A)R^(1B), —C(O)R^(1C), —C(O)OR^(1C), —C(O)NR^(1A)R^(1B),        —OR^(1D), —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹, substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, substituted or unsubstituted heteroaryl; two adjacent R¹        substituents may optionally be joined to form a substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   z1 is an integer from 0 to 4;    -   R² is independently hydrogen or unsubstituted alkyl;    -   L¹ is a bond, unsubstituted alkylene, or unsubstituted        cycloalkylene;    -   each R^(1A), R^(1B), R^(1C), R^(1D) is independently hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;        R^(1A) and R^(1B) substituents bonded to the same nitrogen atom        may optionally be joined to form a substituted or unsubstituted        heterocycloalkyl or substituted or unsubstituted heteroaryl; and        each X¹ is independently —F, —Cl, —Br, or —I.

Embodiment I-4. The compound of one of embodiments I-2 to I-3, whereinRing A is phenyl or 5 to 9 membered heteroaryl.

Embodiment I-5. The compound of one of embodiments I-2 to I-3, whereinRing A is phenyl.

Embodiment I-6. The compound of one of embodiments I-2 to I-3, whereinRing A is 5 to 9 membered heteroaryl.

Embodiment I-7. The compound of one of embodiments I-2 to I-3, whereinRing A is pyridyl.

Embodiment I-8. The compound of one of embodiments I-2 to I-3, whereinRing A is indazolyl.

Embodiment I-9. The compound of one of embodiments I-2 to I-8, whereinR¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN, —SR^(1D),—SO₂R^(1D), —NR^(1A)R^(1B), —OR^(1D), unsubstituted C₁-C₆ alkyl,unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C₃-C₆cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl,unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl; eachR^(1A), R^(1B), R^(1C), R^(1D) is independently hydrogen, unsubstitutedC₁-C₆ alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstitutedC₃-C₆ cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl,unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl;R^(1A) and R^(1B) substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted 3 to 6 memberedheterocycloalkyl or unsubstituted 5 to 6 membered heteroaryl.

Embodiment I-10. The compound of one of embodiments I-2 to I-8, whereinR¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN, —SO₂CH₃,—NHPh, —CH₃, or —CH₂CH₃.

Embodiment I-11. The compound of one of embodiments I-2 to I-10, whereinz1 is 0.

Embodiment I-12. The compound of one of embodiments I-2 to I-10, whereinz1 is 1.

Embodiment I-13. The compound of one of embodiments I-2 to I-10, whereinz1 is 2.

Embodiment I-14. The compound of one of embodiments I-2 to I-13, whereinR² is hydrogen.

Embodiment I-15. The compound of one of embodiments I-2 to I-13, whereinR² is —CH₃.

Embodiment I-16. The compound of one of embodiments I-2 to I-15, whereinL¹ is a bond.

Embodiment I-17. The compound of one of embodiments I-2 to I-15, whereinL¹ is —CH₂—.

Embodiment I-18. The compound of one of embodiments I-2 to I-15, whereinL¹ is —C(CH₃)₂—.

Embodiment I-19. The compound of one of embodiments I-2 to I-15, whereinL¹ is unsubstituted cyclopropylene.

Embodiment I-20. The compound of embodiment I-1, having the formula

Embodiment I-21. The compound of embodiment I-20, wherein

-   -   ring A is an aryl or heteroaryl;    -   R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,        —SR^(1D), —SO₂R^(1D), —NHC(O)NR^(1A)R^(1B), —N(O)₂,        —NR^(1A)R^(1B), —C(O)R^(1C), —C(O)OR^(1C), —C(O)NR^(1A)R^(1B),        —OR^(1D), —OCX¹³, —OCHX¹ ₂, —OCH₂X, substituted or unsubstituted        alkyl, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, substituted        or unsubstituted heteroaryl; two adjacent R¹ substituents may        optionally be joined to form a substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl;    -   z1 is an integer from 0 to 4;    -   L² is a bond, —O—, —C(O)—, —C(O)O—, —OC(O)—, —S—, —SO—, —S(O)₂—,        —NH—, —NHC(O)—, —C(O)NH—, —SO₂NH—, —NHSO₂—, —OC(O)NH—,        —NHC(O)O—, —NHC(O)NH—, —C(O)OCH₂—, —CH₂OC(O)—, —C(O)NHCH₂—,        —CH₂NHC(O)—, —CH₂NHCH₂—, substituted or unsubstituted alkylene,        or substituted or unsubstituted heteroalkylene;    -   each R^(1A), R^(1B), R^(1C), R^(ID) is independently hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;        R^(1A) and R^(1B) substituents bonded to the same nitrogen atom        may optionally be joined to form a substituted or unsubstituted        heterocycloalkyl or substituted or unsubstituted heteroaryl; and        each X¹ is independently —F, —Cl, —Br, or —I.

Embodiment I-22. The compound of one of embodiments I-20 to I-21,wherein Ring A is C₆-C₁₀ aryl or 5 to 9 membered heteroaryl.

Embodiment I-23. The compound of one of embodiments I-20 to I-21,wherein Ring A is phenyl.

Embodiment I-24. The compound of one of embodiments I-20 to I-21,wherein Ring A is naphthyl.

Embodiment I-25. The compound of one of embodiments I-20 to I-21,wherein Ring A is 5 to 9 membered heteroaryl.

Embodiment I-26. The compound of one of embodiments I-20 to I-21,wherein Ring A is indazolyl.

Embodiment I-27. The compound of one of embodiments I-20 to I-26,wherein R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SR^(1D), —N(O)₂, —SO₂R^(1D), —NR^(1A)R^(1B), —OR^(1D), unsubstitutedC₁-C₆ alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstitutedC₃-C₆ cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl,unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl; eachR^(1A), R^(1B), R^(1C), R^(1D) is independently hydrogen, unsubstitutedC₁-C₆ alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstitutedC₃-C₆ cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl,unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl;R^(1A) and R^(1B) substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted 3 to 6 memberedheterocycloalkyl or unsubstituted 5 to 6 membered heteroaryl.

Embodiment I-28. The compound of one of embodiments I-20 to I-26,wherein R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃,—OCHX¹ ₂, —OCH₂X¹, —CN, —N(O)₂, —SO₂CH₃, —N(CH₃)₂, —OCH₃, —OCH₂CH₃,—CH₃, or —CH₂CH₃.

Embodiment I-29. The compound of one of embodiments I-20 to I-28,wherein z1 is 0.

Embodiment I-30. The compound of one of embodiments I-20 to I-28,wherein z1 is 1.

Embodiment I-31. The compound of one of embodiments I-20 to I-28,wherein z1 is 2.

Embodiment I-32. The compound of one of embodiments I-20 to I-31,wherein L² is a bond, —S(O)₂—, —C(O)OCH₂—, —CH₂OC(O)—, —C(O)NHCH₂—,—CH₂NHC(O)—, —CH₂NHCH₂—, or —CH₂—.

Embodiment I-33. The compound of one of embodiments I-20 to I-31,wherein L² is a bond.

Embodiment I-34. The compound of one of embodiments I-20 to I-31,wherein L² is a —S(O)₂—.

Embodiment I-35. The compound of one of embodiments I-20 to I-31,wherein L² is a —C(O)OCH₂—.

Embodiment I-36. The compound of one of embodiments I-20 to I-31,wherein L² is a —C(O)NHCH₂—.

Embodiment I-37. The compound of one of embodiments I-20 to I-31,wherein L² is a —CH₂NHCH₂—.

Embodiment I-38. The compound of one of embodiments I-20 to I-31,wherein L² is a —CH₂—.

Embodiment I-39. The compound of one of embodiments I-1 to I-38, whereinL³ is a bond, —S(O)₂—, —N(R³)—, —O—, —S—, —C(O)—, —C(O)N(R³)—,—N(R³)C(O)—, —N(R³)C(O)NH—, —NHC(O)N(R³)—, —C(O)O—, —OC(O)—, substitutedor unsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene;

-   -   R³ is independently hydrogen, —CX³ ₃, —CHX³ ₂, —CH₂X³,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;        and each X³ is independently —F, —Cl, —Br, or —I.

Embodiment I-40. The compound of one of embodiments I-1 to I-38, whereinL³ is a bond, —S(O)₂—, —NH—, —C(O)NH—, —NHC(O)—, substituted orunsubstituted C₁-C₆ alkylene, substituted or unsubstituted 2 to 6membered heteroalkylene, substituted or unsubstituted C₃-C₆cycloalkylene, substituted or unsubstituted 3 to 6 memberedheterocycloalkylene, substituted or unsubstituted phenylene, orsubstituted or unsubstituted 5 to 6 membered heteroarylene.

Embodiment I-41. The compound of one of embodiments I-1 to I-38, whereinL³ is a bond.

Embodiment I-42. The compound of one of embodiments I-1 to I-38, whereinL³ is substituted or unsubstituted methylene.

Embodiment I-43. The compound of one of embodiments I-1 to I-38, whereinL³ is

Embodiment I-44. The compound of one of embodiments I-1 to I-38, whereinL³ is unsubstituted methylene.

Embodiment I-45. The compound of one of embodiments I-1 to I-38, whereinL³ is

Embodiment I-46. The compound of one of embodiments I-1 to I-45, whereinL⁴ is a bond, —S(O)₂—, —N(R⁴)—, —O—, —S—, —C(O)—, —C(O)N(R⁴)—,—N(R⁴)C(O)—, —N(R⁴)C(O)NH—, —NHC(O)N(R⁴)—, —C(O)O—, —OC(O)—, substitutedor unsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene;

-   -   R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;        and    -   each X⁴ is independently —F, —Cl, —Br, or —I.

Embodiment I-47. The compound of one of embodiments I-1 to I-45, whereinL⁴ is a bond, —S(O)₂—, —NH—, —C(O)NH—, —NHC(O)—, substituted orunsubstituted C₁-C₆ alkylene, substituted or unsubstituted 2 to 6membered heteroalkylene, substituted or unsubstituted C₃-C₆cycloalkylene, substituted or unsubstituted 3 to 6 memberedheterocycloalkylene, substituted or unsubstituted phenylene, orsubstituted or unsubstituted 5 to 6 membered heteroarylene.

Embodiment I-48. The compound of one of embodiments I-1 to I-45, whereinL⁴ is a bond.

Embodiment I-49. The compound of one of embodiments I-1 to I-45, whereinL⁴ is substituted or unsubstituted methylene.

Embodiment I-50. The compound of one of embodiments I-1 to I-45, whereinL⁴ is

Embodiment I-51. The compound of one of embodiments I-1 to I-45, whereinL⁴ is unsubstituted methylene.

Embodiment I-52. The compound of one of embodiments I-1 to I-45, whereinL⁴ is

Embodiment I-53. The compound of one of embodiments I-1 to I-52, whereinR⁵ is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl.

Embodiment I-54. The compound of one of embodiments I-1 to I-52, whereinR⁵ is independently substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted 3 to 6membered heterocycloalkyl, substituted or unsubstituted phenyl, orsubstituted or unsubstituted 5 to 6 membered heteroaryl.

Embodiment I-55. The compound of one of embodiments I-1 to I-52, whereinR⁵ is independently substituted or unsubstituted 3 to 6 memberedheterocycloalkyl or substituted or unsubstituted 5 to 6 memberedheteroaryl.

Embodiment I-56. The compound of one of embodiments I-1 to I-52, whereinR⁵ is independently 3 to 6 membered heterocycloalkyl or 5 to 6 memberedheteroaryl; optionally substituted with one or more independentsubstituent groups, a size-limited substituent groups, or lowersubstituent groups.

Embodiment I-57. The compound of one of embodiments I-1 to I-52, whereinR⁵ is

Embodiment I-58. The compound of one of embodiments I-1 to I-52, whereinR⁵ is E.

Embodiment I-59. The compound of embodiment I-58, wherein E is acovalent histidine binding moiety.

Embodiment I-60. The compound embodiment I-59, wherein E is

-   -   wherein R¹⁶ is independently hydrogen, halogen, CX¹⁶ ₃, —CHX¹⁶        ₂, —CH₂X¹⁶, —CN, —SO_(n16)R^(16D), —SO_(v16)NR^(16A)R^(16B),        —NHNR^(16A)R^(16B), —ONR^(16A)R^(16B),        —NHC═(O)NHNR^(16A)R^(16B), —NHC(O)NR^(16A)R^(16B), —N(O)_(m16),        —NR^(16A)R^(16B), —C(O)R^(16C), —C(O)—OR^(16C),        —C(O)NR^(16A)R^(16B), —OR¹⁶D,        —NR^(16A)SO₂R^(16D)—NR^(16A)C(O)R^(16C), —NR^(16A)C(O)OR^(16C),        —NR^(16A)OR^(16C), —OCX¹⁶ ₃, —OCHX¹⁶ ₂, substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, substituted or unsubstituted heteroaryl;    -   R¹⁷ is independently hydrogen, halogen, CX¹⁷ ₃, —CHX¹⁷ ₂,        —CH₂X^(1.7), —CN, —SO_(n1)7R_(17D), —SO₇NR^(17A)R^(17B),        —NHNR^(17A)R^(17B), —ONR^(17A)R^(17B),        —NHC═(O)NHNR^(17A)R^(17B), —NHC(O)NR^(17A)R^(17B), —N(O)_(m17),        —NR^(17A)R^(17B), C(O)R^(17C), —C(O)—OR^(17C),        C(O)NR^(17A)R^(17B), —OR^(17D), —NR^(17A)SO₂R^(17D),        —NR^(17A)C(O)R^(17C), —NR^(17A)C(O)OR^(17C), —NR^(17A)OR^(17C),        —OCX¹⁷ ₃, —OCHX¹⁷ ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, substituted        or unsubstituted heteroaryl;    -   R¹⁸ is independently hydrogen, halogen, CX¹⁸ ₃, —CHX¹⁸ ₂,        —CH₂X¹⁸, —CN, —SO_(n18)R^(18D), —SO_(v18)NR^(18A)R^(18B),        —NHNR^(18A)R^(18B), —ONR^(18A)R^(18B),        —NHC═(O)NHNR^(18A)R^(18B), —NHC(O)NR^(18A)R^(18B), —N(O)_(m18),        —NR^(18A)R^(18B), C(O)R^(18C), —C(O)—OR^(18C),        —C(O)NR^(18A)R^(18B), —OR^(18D), —NR^(18A)SO₂R^(18D),        —NR^(18A)C(O)R^(18C), —NR^(18A)C(O)OR^(18C), —NR^(18A)OR^(18C),        —OCX¹⁸ ₃, —OCHX¹⁸ ₂, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, substituted        or unsubstituted heteroaryl;    -   R¹⁹ is independently hydrogen, halogen, CX¹⁹ ₃, —CHX¹⁹ ₂,        —CH₂X¹⁹, —CN, —SO_(n19)R^(19D), —SO_(v19)NR^(19A)R^(19B),        —NHNR^(19A)R^(19B), —ONR^(19A)R^(19B),        —NHC═(O)NHNR^(19A)R^(19B), —NHC(O)NR^(19A)R^(19B), —N(O)_(m19),        —NR^(19A)R^(19B), —C(O)R^(19C), —C(O)—OR^(19C),        —C(O)NR^(19A)R^(19B),        —OR^(19D)—NR^(19A)SO₂R^(19D)—NR^(19A)C(O)R^(19C),        —NR^(19A)C(O)OR^(19C), —NR^(19A)OR^(19C), —OCX¹⁹ ₃, —OCHX¹⁹ ₂,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl;    -   R^(16A), R^(16B), R^(16C), R^(16D), R^(17A), R^(17B), R^(17C),        R^(17D), R^(18A), R^(18B), R^(18C), R^(18D), R^(19A), R^(19B),        R^(19C), R^(19D), are independently hydrogen, halogen, —CX₃,        —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,        —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,        —NHC(O)OH, —NHOH, —OCX₃, —OCHX₂, —CHX₂, —CH₂X, substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl; R^(16A) and        R^(16B) substituents bonded to the same nitrogen atom may        optionally be joined to form a substituted or unsubstituted        heterocycloalkyl or substituted or unsubstituted heteroaryl;        R^(17A) and R^(17B) substituents bonded to the same nitrogen        atom may optionally be joined to form a substituted or        unsubstituted heterocycloalkyl or substituted or unsubstituted        heteroaryl; R^(18A) and R^(18B) substituents bonded to the same        nitrogen atom may optionally be joined to form a substituted or        unsubstituted heterocycloalkyl or substituted or unsubstituted        heteroaryl; R^(19A) and R^(19B) substituents bonded to the same        nitrogen atom may optionally be joined to form a substituted or        unsubstituted heterocycloalkyl or substituted or unsubstituted        heteroaryl; each X, X¹⁶, X¹⁷, X¹⁸ and X¹⁹ is independently —F,        —Cl, —Br, or —I; n16, n17, n18, n19, v16, v17, v18, and v19 are        independently an integer from 0 to 4; and m16, m17, m18, and m19        are independently an integer from 1 to 2.

Embodiment I-61. The compound embodiment I-59, wherein E is

Embodiment I-62. The compound of one of embodiments I-1 to I-61, wherein-L³-L⁴-R⁵ is not

Embodiment I-63. A pharmaceutical composition comprising the compound ofany one of embodiments I-1 to I-62 and a pharmaceutically acceptableexcipient.

Embodiment I-64. A method of reducing the level of activity of a K-Rasprotein, said method comprising contacting the K-Ras protein with acompound of one of embodiments 1 to 62.

Embodiment I-65. The method of embodiment I-64, wherein the compoundcontacts the K-Ras amino acid corresponding to H95 of human K-Ras.

Embodiment I-66. The method of embodiment I-64, wherein the compoundcovalently binds the K-Ras amino acid corresponding to H95 of humanK-Ras.

Embodiment I-67. The method of one of embodiments I-64 to I-66, whereinthe K-Ras protein is human K-Ras 4A.

Embodiment I-68. The method of one of embodiments I-64 to I-66, whereinthe K-Ras protein is human K-Ras 4B.

Embodiment I-69. The method of one of embodiments I-64 to I-66,comprising reducing the level of activity of both human K-Ras 4A andhuman K-Ras 4B.

Embodiment I-70. The method of one of embodiments I-64 to I-69, whereinthe activity of the K-Ras protein is increasing cell proliferation.

Embodiment I-71. The method of one of embodiments I-64 to I-70, whereinthe activity of the K-Ras protein is not GTPase activity.

Embodiment I-72. A method for treating cancer, said method comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound of one of embodiments I-1 to I-62.

Embodiment I-73. The method of embodiment I-72, wherein said cancer ispancreatic cancer, lung cancer, or colorectal cancer.

Embodiment I-74. The method of embodiment I-72, wherein said cancer isassociated with K-Ras activity.

Embodiment I-75. Use of a compound of one of Embodiments I-1 to I-62 inthe manufacture of a medicament for reducing the level of activity of aK-Ras protein in a subject in need thereof.

Embodiment I-76. The use of Embodiment I-75, wherein the compoundcontacts the K-Ras amino acid corresponding to H95 of human K-Ras.

Embodiment I-77. The use of Embodiment I-75, wherein the compoundcovalently binds the K-Ras amino acid corresponding to H95 of humanK-Ras.

Embodiment I-78. The use of one of Embodiments I-75 to I-77, wherein theK-Ras protein is human K-Ras 4A.

Embodiment I-79. The use of one of Embodiments I-75 to I-77, wherein theK-Ras protein is human K-Ras 4B.

Embodiment I-80. The use of one of Embodiments I-75 to I-77, comprisingreducing the level of activity of both human K-Ras 4A and human K-Ras4B.

Embodiment I-81. The use of one of Embodiments I-75 to I-80, wherein theactivity of the K-Ras protein is increasing cell proliferation.

Embodiment I-82. The use of one of Embodiments I-75 to I-81, wherein theactivity of the K-Ras protein is not GTPase activity.

Embodiment I-83. Use of a compound of one of Embodiments I-1 to I-62 inthe manufacture of a medicament for treating cancer in a subject in needthereof.

Embodiment I-84. The use of Embodiment I-83, wherein said cancer ispancreatic cancer, lung cancer, or colorectal cancer.

Embodiment I-85. The use of Embodiment I-83, wherein said cancer isassociated with K-Ras activity.

Embodiment I-86. A compound of one of Embodiments I-1 to I-62 for use amethod for reducing the level of activity of a K-Ras protein in asubject in need thereof.

Embodiment I-87. The compound for use of Embodiment I-86, wherein thecompound contacts the K-Ras amino acid corresponding to H95 of humanK-Ras.

Embodiment I-88. The compound for use of Embodiment I-86, wherein thecompound covalently binds the K-Ras amino acid corresponding to H95 ofhuman K-Ras.

Embodiment I-89. The compound for use of one of Embodiments I-86 toI-88, wherein the K-Ras protein is human K-Ras 4A.

Embodiment I-90. The compound for use of one of Embodiments I-86 toI-88, wherein the K-Ras protein is human K-Ras 4B.

Embodiment I-91. The compound for use of one of Embodiments I-86 toI-88, comprising reducing the level of activity of both human K-Ras 4Aand human K-Ras 4B.

Embodiment I-92. The compound for use of one of Embodiments I-86 toI-91, wherein the activity of the K-Ras protein is increasing cellproliferation.

Embodiment I-93. The compound for use of one of Embodiments I-86 toI-92, wherein the activity of the K-Ras protein is not GTPase activity.

Embodiment I-94. A compound of one of Embodiments I-1 to I-62 for use ina method for treating cancer in a subject in need thereof.

Embodiment I-95. The compound for use of Embodiment I-94, wherein saidcancer is pancreatic cancer, lung cancer, or colorectal cancer.

Embodiment I-96. The compound for use of Embodiment I-94, wherein saidcancer is associated with K-Ras activity.

Embodiment II-1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is an aryl or heteroaryl;

R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B), —NHNR^(1A)R^(1B),—ONR^(1A)R^(1B), —NHC═(O)NHNR^(1A)R^(1B), —NHC(O)NR^(1A)R^(1B),—N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C), —C(O)—OR^(1C),—C(O)NR^(1A)R^(1B), —OR^(1D), —NR^(1A)SO₂R^(1D), —NR^(1A)C(O)R^(1C),—NR^(1A)C(O)OR^(1C), —NR^(1A)OR^(1C), —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl; two adjacent R¹ substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z1 is an integer from 0 to 4;

R² is independently hydrogen, —CX² ₃, —CHX² ₂, —CH₂X², —C(O)R^(2A),—C(O)OR^(2A), —C(O)NR^(2A)R^(2B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl;

L¹ is a bond, substituted or unsubstituted alkylene, substituted orunsubstituted cycloalkylene, or

L³ is a bond, —S(O)₂—, —N(R³)—, —O—, —S—, —C(O)—, —C(O)N(R³)—,—N(R³)C(O)—, —N(R³)C(O)NH—, —NHC(O)N(R³)—, —C(O)O—, —OC(O)—, substitutedor unsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene;

R³ is independently hydrogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —C(O)R^(3A),—C(O)OR^(3A), —C(O)NR^(3A)R^(3B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

L⁴ is a bond, —S(O)₂—, —N(R⁴)—, —O—, —S—, —C(O)—, —C(O)N(R⁴)—,—N(R⁴)C(O)—, —N(R⁴)C(O)NH—, —NHC(O)N(R⁴)—, —C(O)O—, —OC(O)—, substitutedor unsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene;

R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —C(O)R^(4A),—C(O)OR⁴A —C(O)NR^(4A)R^(4B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁵ is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, or E;

E is a histidine binding moiety;

each R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(3A), R^(3B),R^(4A), and R^(4B) is independently hydrogen, —CX₃, —CN, —COOH, —CONH₂,—CHX₂, —CH₂X, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^(1A) and R^(1B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

R^(2A) and R^(2B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

R^(3A) and R^(3B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

R^(4A) and R^(4B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X¹, X², X³, and X⁴ is independently —F, —Cl, —Br, or —I;

n1 is independently an integer from 0 to 4; and

m1 and v1 are independently 1 or 2.

Embodiment II-2. The compound of embodiment II-1, wherein the compoundis of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is an aryl or heteroaryl;

R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B), —NHNR^(1A)R^(1B),—ONR^(1A)R^(1B), —NHC═(O)NHNR^(1A)R^(1B), —NHC(O)NR^(1A)R^(1B),—N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C), —C(O)—OR^(1C),—C(O)NR^(1A)R^(1B), —OR^(1D), —NR^(1A)SO₂R^(1D), —NR^(1A)C(O)R^(1C),—NR^(1A)C(O)OR^(1C), —NR^(1A)OR^(1C), —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl;

two adjacent R¹ substituents may optionally be joined to form asubstituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

z1 is an integer from 0 to 4;

R² is independently hydrogen, —CX² ₃, —CHX² ₂, —CH₂X², —C(O)R^(2A),—C(O)OR^(2A), —C(O)NR^(2A)R^(2B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl;

L¹ is a bond, substituted or unsubstituted alkylene, substituted orunsubstituted cycloalkylene, or

L³ is a bond, —S(O)₂—, —N(R³)—, —O—, —S—, —C(O)—, —C(O)N(R³)—,—N(R³)C(O)—, —N(R³)C(O)NH—, —NHC(O)N(R³)—, —C(O)O—, —OC(O)—, substitutedor unsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene;

R³ is independently hydrogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —C(O)R^(3A),—C(O)OR^(3A), —C(O)NR^(3A)R^(3B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

L⁴ is a bond, —S(O)₂—, —N(R⁴)—, —O—, —S—, —C(O)—, —C(O)N(R⁴)—,—N(R⁴)C(O)—, —N(R⁴)C(O)NH—, —NHC(O)N(R⁴)—, —C(O)O—, —OC(O)—, substitutedor unsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene;

R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —C(O)R^(4A),—C(O)OR^(4A), —C(O)NR^(4A)R^(4B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁵ is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, or E;

E is a histidine binding moiety;

each R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(3A), R^(3B),R^(4A), and R^(4B) is independently hydrogen, —CX₃, —CN, —COOH, —CONH₂,—CHX₂, —CH₂X, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^(1A) and R^(1B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

R^(2A) and R^(2B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

R^(3A) and R^(3B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

R^(4A) and R^(4B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X¹, X², X³, and X⁴ is independently —F, —Cl, —Br, or —I;

n1 is independently an integer from 0 to 4; and

m1 and v1 are independently 1 or 2.

Embodiment II-3. The compound of embodiment II-1 or II-2, or apharmaceutically acceptable salt thereof, wherein:

Ring A is heteroaryl;

R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B), —NHNR^(1A)R^(1B),—ONR^(1A)R^(1B), —NHC═(O)NHNR^(1A)R^(1B), —NHC(O)NR^(1A)R^(1B),—N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C), —C(O)—OR^(1C),—C(O)NR^(1A)R^(1B), —OR^(1D), —NR^(1A)SO₂R^(1D), —NR^(1A)C(O)R^(1C),—NR^(1A)C(O)OR^(1C), —NR^(1A)OR^(1C), —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl;

two adjacent R¹ substituents may optionally be joined to form asubstituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

z1 is an integer from 0 to 4;

R² is independently hydrogen, —CX² ₃, —CHX² ₂, —CH₂X², —C(O)R^(2A),—C(O)OR^(2A), —C(O)NR^(2A)R^(2B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl;

L¹ is a bond, substituted or unsubstituted alkylene, substituted orunsubstituted cycloalkylene, or

L³ is a bond, —S(O)₂—, —N(R³)—, —O—, —S—, —C(O)—, —C(O)N(R³)—,—N(R³)C(O)—, —N(R³)C(O)NH—, —NHC(O)N(R³)—, —C(O)O—, —OC(O)—, substitutedor unsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene;

R³ is independently hydrogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —C(O)R^(3A),—C(O)OR^(3A), —C(O)NR^(3A)R^(3B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

L⁴ is a bond, —S(O)₂—, —N(R⁴)—, —O—, —S—, —C(O)—, —C(O)N(R⁴)—,—N(R⁴)C(O)—, —N(R⁴)C(O)NH—, —NHC(O)N(R⁴)—, —C(O)O—, —OC(O)—, substitutedor unsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene;

R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —C(O)R^(4A),—C(O)OR^(4A), —C(O)NR^(4A)R^(4B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁵ is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, or E;

E is a histidine binding moiety;

each R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(3A), R^(3B),R^(4A), and R^(4B) is independently hydrogen, —CX₃, —CN, —COOH, —CONH₂,—CHX₂, —CH₂X, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^(1A) and R^(1B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

R^(2A) and R^(2B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

R^(3A) and R^(3B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

R^(4A) and R^(4B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X¹, X², X³, and X⁴ is independently —F, —Cl, —Br, or —I;

n1 is independently an integer from 0 to 4; and

m1 and v1 are independently 1 or 2.

Embodiment II-4. The compound of any one of embodiments II-1 to II-3, ora pharmaceutically acceptable salt thereof, wherein:

Ring A is heteroaryl;

R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B), —ONR^(1A)R^(1B), —N(O)_(m1),—NR^(1A)R^(1B), —OR^(1D), —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

z1 is an integer from 0 to 4;

R² is independently hydrogen, —CX² ₃, —CHX² ₂, —CH₂X², or substituted orunsubstituted alkyl;

L¹ is a bond, substituted or unsubstituted alkylene, or

L³ is a bond or substituted or unsubstituted alkylene;

L⁴ is a bond, —O—, —N(R⁴)—, or —C(O)—;

R⁴ is hydrogen or substituted or unsubstituted alkyl;

R⁵ is substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each R^(1A), R^(1B), R^(1C), and R^(1D) is independently hydrogen, —CX₃,—CHX₂, —CH₂X, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

each X, X¹, and X² are independently —F, —Cl, —Br, or —I; n1 isindependently an integer from 0 to 4; and m1 and v1 are independently 1or 2.

Embodiment II-5. The compound of Embodiment II-1 or II-2, or apharmaceutically acceptable salt thereof, wherein when Ring A is aryl,L¹ is a bond, substituted or unsubstituted alkylene, or substituted orunsubstituted cycloalkylene.

Embodiment II-6. The compound of embodiment II-1 or II-2, wherein thecompound is of Formula (I), or a pharmaceutically acceptable saltthereof, wherein:

Ring A is aryl;

R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B), —NHNR^(1A)R^(1B),—ONR^(1A)R^(1B), —NHC═(O)NHNR^(1A)R^(1B), —NHC(O)NR^(1A)R^(1B),—N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C), —C(O)—OR^(1C),—C(O)NR^(1A)R^(1B), —OR^(1D), —NR^(1A)SO₂R^(1D), —NR^(1A)C(O)R^(1C),—NR^(1A)C(O)OR^(1C), —NR^(1A)OR^(1C), —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl;

two adjacent R¹ substituents may optionally be joined to form asubstituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

z1 is an integer from 0 to 4;

R² is independently hydrogen, —CX² ₃, —CHX² ₂, —CH₂X², —C(O)R^(2A),—C(O)OR^(2A), —C(O)NR^(2A)R^(2B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl;

L¹ is a bond, substituted or unsubstituted alkylene, or substituted orunsubstituted cycloalkylene;

L³ is a bond, —S(O)₂—, —N(R³)—, —O—, —S—, —C(O)—, —C(O)N(R³)—,—N(R³)C(O)—, —N(R³)C(O)NH—, —NHC(O)N(R³)—, —C(O)O—, —OC(O)—, substitutedor unsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene;

R³ is independently hydrogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —C(O)R^(3A),—C(O)OR^(3A), —C(O)NR^(3A)R^(3B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

L⁴ is a bond, —S(O)₂—, —N(R⁴)—, —O—, —S—, —C(O)—, —C(O)N(R⁴)—,—N(R⁴)C(O)—, —N(R⁴)C(O)NH—, —NHC(O)N(R⁴)—, —C(O)O—, —OC(O)—, substitutedor unsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene;

R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —C(O)R^(4A),—C(O)OR^(4A), —C(O)NR^(4A)R^(4B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁵ is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, or E;

E is a histidine binding moiety;

each R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(3A), R^(3B),R^(4A), and R^(4B) is independently hydrogen, —CX₃, —CN, —COOH, —CONH₂,—CHX₂, —CH₂X, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^(1A) and R^(1B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

R^(2A) and R^(2B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

R^(3A) and R^(3B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

R^(4A) and R^(4B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X¹, X², X³, and X⁴ is independently —F, —Cl, —Br, or —I;

n1 is independently an integer from 0 to 4; and

m1 and v1 are independently 1 or 2.

Embodiment II-7. The compound of any one of embodiments II-1, II-2, orII-5, or a pharmaceutically acceptable salt thereof, wherein:

Ring A is aryl;

R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B), —ONR^(1A)R^(1B), —N(O)_(m1),—NR^(1A)R^(1B), —OR^(1D), —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

z1 is an integer from 0 to 4;

R² is independently hydrogen, —CX² ₃, —CHX² ₂, —CH₂X², or substituted orunsubstituted alkyl;

L¹ is a bond, or substituted or unsubstituted alkylene;

L³ is a bond or substituted or unsubstituted alkylene;

L⁴ is a bond, —O—, —N(R⁴)—, or —C(O)—;

R⁴ is hydrogen or substituted or unsubstituted alkyl;

R⁵ is substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each R^(1A), R^(1B), R^(1C), and R^(1D) is independently hydrogen, —CX₃,—CHX₂, —CH₂X, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

each X, X¹, and X² are independently —F, —Cl, —Br, or —I;

n1 is independently an integer from 0 to 4; and

m1 and v1 are independently 1 or 2.

Embodiment II-8. The compound of any one of embodiments II-1 to II-7, ora pharmaceutically acceptable salt thereof, wherein L¹ is unsubstitutedalkylene.

Embodiment II-9. The compound of any one of embodiments 1 to 7, or apharmaceutically acceptable salt thereof, wherein L¹ is alkylenesubstituted with cycloalkyl.

Embodiment II-10. The compound of any one of embodiments II-1 to II-7,or a pharmaceutically acceptable salt thereof, wherein L¹ is a bond.

Embodiment II-11. The compound of embodiment II-1, wherein the compoundis of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is an aryl or heteroaryl;

R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B), —NHNR^(1A)R^(1B),—ONR^(1A)R^(1B), —NHC═(O)NHNR^(1A)R^(1B), —NHC(O)NR^(1A)R^(1B),—N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C), —C(O)—OR^(1C),—C(O)NR^(1A)R^(1B), —OR^(1D), —NR^(1A)SO₂R^(1D), —NR^(1A)C(O)R^(1C),—NR^(1A)C(O)OR^(1C), —NR^(1A)OR^(1C), —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl; two adjacent R¹ substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z1 is an integer from 0 to 4;

R² is independently hydrogen, —CX² ₃, —CHX² ₂, —CH₂X², —C(O)R^(2A),—C(O)OR^(2A), —C(O)NR^(2A)R^(2B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl;

L³ is a bond, —S(O)₂—, —N(R³)—, —O—, —S—, —C(O)—, —C(O)N(R³)—,—N(R³)C(O)—, —N(R³)C(O)NH—, —NHC(O)N(R³)—, —C(O)O—, —OC(O)—, substitutedor unsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene;

R³ is independently hydrogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —C(O)R^(3A),—C(O)OR^(3A), —C(O)NR^(3A)R^(3B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

L⁴ is a bond, —S(O)₂—, —N(R⁴)—, —O—, —S—, —C(O)—, —C(O)N(R⁴)—,—N(R⁴)C(O)—, —N(R⁴)C(O)NH—, —NHC(O)N(R⁴)—, —C(O)O—, —OC(O)—, substitutedor unsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene;

R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —C(O)R^(4A),—C(O)OR^(4A), —C(O)NR^(4A)R^(4B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁵ is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, or E;

E is a histidine binding moiety;

each R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(3A), R^(3B),R^(4A), and R^(4B) is independently hydrogen, —CX₃, —CN, —COOH, —CONH₂,—CHX₂, —CH₂X, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^(1A) and R^(1B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

R^(2A) and R^(2B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

R^(3A) and R^(3B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

R^(4A) and R^(4B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X¹, X², X³, and X⁴ is independently —F, —Cl, —Br, or —I; n1 isindependently an integer from 0 to 4; and m1 and v1 are independently 1or 2.

Embodiment II-12. The compound of embodiment II-11, or apharmaceutically acceptable salt thereof, wherein:

Ring A is an aryl or heteroaryl;

R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B), —ONR^(1A)R^(1B), —N(O)_(m1),—NR^(1A)R^(1B), —OR^(1D), —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

z1 is an integer from 0 to 4;

L² is —S—, —SO—, —S(O)₂—, —NHC(O)—, —C(O)NH—, —C(O)NHCH₂—, —CH₂NHC(O)—,substituted or unsubstituted alkylene, or substituted or unsubstitutedheteroalkylene;

L³ is a bond or substituted or unsubstituted alkylene;

L⁴ is a bond, —O—, —N(R⁴)—, or —C(O)—;

R⁴ is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —C(O)R^(4A),—C(O)OR^(4A), —C(O)NR^(4A)R^(4B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ issubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; eachR^(1A), R^(1B), R^(1C), R^(1D), R^(4A), and R^(4B) is independentlyhydrogen, —X₃, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; each X, X¹, X⁴ is independently —F, —Cl, —Br,or —I; n1 is independently an integer from 0 to 4; and m1 and v1 areindependently 1 or 2.

Embodiment II-13. The compound of any one of embodiments II-1, II-11, orII-12, or a pharmaceutically acceptable salt thereof, wherein L² is—S(O)₂—, —C(O)NH—, —C(O)NHCH₂—, substituted or unsubstituted alkylene,or substituted or unsubstituted heteroalkylene.

Embodiment II-14. The compound of any one of embodiments II-1, II-11, orII-12, or a pharmaceutically acceptable salt thereof, wherein L² issubstituted heteroalkylene.

Embodiment II-15. The compound of any one of embodiments II-1, II-11, orII-12, or a pharmaceutically acceptable salt thereof, wherein L² is—S(O)₂— or —C(O)NHCH₂—.

Embodiment II-16. The compound of any one of embodiments II-1 to II-15,or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently halogen, —OR^(1D), —NR^(1A)R^(1B), —CN, or substituted orunsubstituted alkyl, wherein each R^(1A), R^(1B), and R^(1D) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

Embodiment II-17. The compound of any one of embodiments II-1 to II-16,or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently halogen, —CN, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCHX¹ ₂,—OCH₂X¹, —OR^(1D), or —NR^(1A)R^(1B), wherein each R^(1A), R^(1B), andR^(1D) is independently hydrogen, substituted or unsubstituted alkyl, orsubstituted or unsubstituted aryl.

Embodiment II-18. The compound of any one of embodiments II-1 to II-17,or a pharmaceutically acceptable salt thereof, wherein R⁵ is substitutedC₁-C₆ alkyl, substituted or unsubstituted 3- to 6-memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl.

Embodiment II-19. The compound of embodiment II-18, or apharmaceutically acceptable salt thereof, wherein R⁵ is R¹³-substitutedC₁-C₆ alkyl, wherein R¹³ is independently selected from the groupconsisting of —OR¹⁴, oxo, and —S(O)₂R¹⁴, wherein each R¹⁴ isindependently hydrogen, halogen, or substituted or unsubstituted aryl.

Embodiment II-20. The compound of any one of embodiments II-1 to II-18,or a pharmaceutically acceptable salt thereof, wherein R⁵ is substitutedor unsubstituted 3- to 6-membered heterocycloalkyl.

Embodiment II-21. The compound of any one of embodiments II-1 to II-20,or a pharmaceutically acceptable salt thereof, wherein R⁵ is:

Embodiment II-22. The compound of any one of embodiments II-1 to II-18,or a pharmaceutically acceptable salt thereof, wherein R⁵ is:

wherein R¹³ is hydrogen, halogen, substituted or unsubstituted alkyl;and z13 is an integer from 0 to 3.

Embodiment II-23. The compound of any one of embodiments II-1 to II-18,II-21, or II-22, or a pharmaceutically acceptable salt thereof, whereinR⁵ is:

Embodiment II-24. The compound of any one of embodiments II-1, or II-11to II-23, or a pharmaceutically acceptable salt thereof, wherein Ring Ais aryl.

Embodiment II-25. The compound of any one of embodiments II-1, II-2, orII-6 to II-24, or a pharmaceutically acceptable salt thereof, whereinRing A is phenyl.

Embodiment II-26. The compound of any one of embodiments II-1 to II-4,or II-11 to II-23, or a pharmaceutically acceptable salt thereof,wherein Ring A is a 5- to 10-membered heteroaryl.

Embodiment II-27. The compound of embodiment II-26, or apharmaceutically acceptable salt thereof, wherein Ring A is indolinyl,indazolyl, benzimidazolyl, benzoxazolyl, azaindolyl, purinyl, indolyl,pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,benzofuranyl, indolyl, or benzothienyl.

Embodiment II-28. The compound of embodiment II-27, or apharmaceutically acceptable salt thereof, wherein Ring A is indolyl.

Embodiment II-29. The compound of any one of embodiments II-1 to II-28,or a pharmaceutically acceptable salt thereof, wherein L³ is substitutedor unsubstituted C₁-C₈ alkylene.

Embodiment II-30. The compound of any one of embodiments II-1 to II-29,or a pharmaceutically acceptable salt thereof, wherein L³ isunsubstituted methylene.

Embodiment II-31. The compound of any one of embodiments II-1 to II-30,or a pharmaceutically acceptable salt thereof, wherein L³ is

Embodiment II-32. The compound of embodiment II-1 or II-2, wherein thecompound is:

or a pharmaceutically acceptable salt of any of these.

Embodiment II-33. The compound of embodiment II-1 or II-2, wherein thecompound is:

or a pharmaceutically acceptable salt of any of these.

Embodiment II-34. The compound of embodiment II-1 or II-11, wherein thecompound is:

or a pharmaceutically acceptable salt of any of these.

Embodiment II-35. The compound of embodiment II-1 or II-11, wherein thecompound is:

or a pharmaceutically acceptable salt of any of these.

Embodiment II-36A pharmaceutical composition comprising the compound ofany one of embodiments II-1 to II-35, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient.

Embodiment II-37A method of reducing the level of a K-Ras protein in asubject in need thereof, comprising administering to the subject acompound of one of embodiments II-1 to II-35, or a pharmaceuticallyacceptable salt thereof.

Embodiment II-38. A method of reducing the activity level of a K-Rasprotein in a subject in need thereof, comprising administering to thesubject a compound of one of embodiments II-1 to II-35, or apharmaceutically acceptable salt thereof.

Embodiment II-39. The method of embodiment II-37 or II-38, wherein thecompound or pharmaceutically acceptable salt thereof contacts the aminoacid corresponding to H95 of human K-Ras.

Embodiment II-40. The method of embodiment II-37 or II-38, wherein thecompound or pharmaceutically acceptable salt thereof covalently bindsthe amino acid corresponding to H95 of human K-Ras.

Embodiment II-41. The method of any one of embodiments II-37 to II-40,wherein the K-Ras protein is human K-Ras 4A.

Embodiment II-42. The method of any one of embodiments II-37 to II-40,wherein the K-Ras protein is human K-Ras 4B.

Embodiment II-43. The method of any one of embodiments II-37 or II-39 toII-42, comprising reducing the level of both human K-Ras 4A and humanK-Ras 4B.

Embodiment II-44. The method of any one of embodiments II-38 to II-42,comprising reducing the activity level of both human K-Ras 4A and humanK-Ras 4B.

Embodiment II-45. A method for treating a disorder in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of any one of embodiments II-1 to II-35,or a pharmaceutically acceptable salt thereof.

Embodiment II-46. The method of embodiment II-45, wherein the disorderis cancer.

Embodiment II-47. The method of embodiment II-46, wherein the cancer ispancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma,rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia,malignant peripheral nerve sheath tumors, gastrointestinal stromaltumors, somatostatinomas, pheochromocytomas, or breast cancer.

Embodiment II-48. The method of embodiment II-45, wherein the disorderis neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneoussyndrome, or Legius syndrome.

Embodiment II-49. The method of any one of embodiments II-45 to II-48,wherein the disorder is associated with a mutation of K-Ras.

Embodiment II-50. Use of a compound of any one of embodiments II-1 toII-35, or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for reducing the level of a K-Ras protein in a subjectin need thereof.

Embodiment II-51. Use of a compound of any one of embodiments II-1 toII-35, or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for reducing the activity level of a K-Ras protein in asubject in need thereof.

Embodiment II-52. The use of embodiment II-50 or II-51, wherein theK-Ras protein is human K-Ras 4B.

Embodiment II-53. Use of a compound of any one of embodiments II-1 toII-35, or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for treating a disorder in a subject in need thereof.

Embodiment II-54. The use of embodiment II-53, wherein the disorder iscancer.

Embodiment II-55. The use of embodiment II-54, wherein the cancer ispancreatic cancer, lung cancer, colorectal cancer, optic pathway glioma,rhabdomyosarcoma, neuroblastoma, juvenile myelomonocytic leukemia,malignant peripheral nerve sheath tumors, gastrointestinal stromaltumors, somatostatinomas, pheochromocytomas, or breast cancer.

Embodiment II-56. The use of embodiment II-53, wherein the disorder isneurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneoussyndrome, or Legius syndrome.

Embodiment II-57. The use of any one of embodiments II-53 to II-56,wherein the disorder is associated with a mutation of K-Ras.

Embodiment II-58. A compound according to any one of embodiments II-1 toII-35, or a pharmaceutically acceptable salt thereof, for use in amethod of reducing the level of a K-Ras protein in a subject in needthereof.

Embodiment II-59. A compound according to any one of embodiments II-1 toII-35, or a pharmaceutically acceptable salt thereof, for use in amethod of reducing the activity level of a K-Ras protein in a subject inneed thereof.

Embodiment II-60. The compound for use of embodiment II-58 or II-59,wherein the K-Ras protein is human K-Ras 4B.

Embodiment II-61. A compound according to any one of embodiments II-1 toII-35, or a pharmaceutically acceptable salt thereof, for use in amethod of treating a disorder in a subject in need thereof.

Embodiment II-62. The compound for use in embodiment II-61, wherein thedisorder is cancer.

Embodiment II-63. The compound for use of embodiment II-62, wherein thecancer is pancreatic cancer, lung cancer, colorectal cancer, opticpathway glioma, rhabdomyosarcoma, neuroblastoma, juvenile myelomonocyticleukemia, malignant peripheral nerve sheath tumors, gastrointestinalstromal tumors, somatostatinomas, pheochromocytomas, or breast cancer.

Embodiment II-64. The compound for use of embodiment II-61, wherein thedisorder is neurofibromatosis type 1, Noonan syndrome,cardio-facio-cutaneous syndrome, or Legius syndrome.

Embodiment II-65. The compound for use of any one of embodiments II-61to II-64, wherein the disorder is associated with a mutation of K-Ras.

What is claimed is:
 1. A compound having formula (II):

or a pharmaceutically acceptable salt thereof, wherein: Ring A isphenyl, indolinyl, indazolyl, benzimidazolyl, benzoxazolyl, azaindolyl,purinyl, indolyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, benzofuranyl, benzothienyl,

R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B), —NHNR^(1A)R^(1B),—ONR^(1A)R^(1B), —NHC=(O)NHNR^(1A)R^(1B), —NHC(O)NR^(1A)R^(1B),—N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C), —C(O)—OR^(1C),—C(O)NR^(1A)R^(1B), —OR^(1D), —NR^(1A)SO₂R^(1D), —NR^(1A)C(O)R^(1C),—NR^(1A)C(O)OR^(1C), —NR^(1A)OR^(1C), —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, or substituted orunsubstituted heterocycloalkyl; or two adjacent R¹ substituents mayoptionally be joined to form a substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; z1 is aninteger from 0 to 4; L² is —S(O)₂—, —C(O)NH—, or —C(O)NHCH₂—; L³ is abond, —S(O)₂—, —N(R³)—, —O—, —S—, —C(O)—, —C(O)N(R³)—, —N(R³)C(O)—,—N(R³)C(O)NH—, —NHC(O)N(R³)—, —C(O)O—, —OC(O)—, unsubstituted alkylene,unsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted arylene, or unsubstitutedheteroarylene; R³ is independently hydrogen, —CX³ ₃, —CHX³ ₂, —CH₂X³,—C(O)R^(3A), —C(O)OR^(3A), —C(O)NR^(3A)R^(3B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; L⁴ is a bond, —S(O)₂—, —N(R⁴)—, —O—, —S—,—C(O)—, —C(O)N(R⁴)—, —N(R⁴)C(O)—, —N(R⁴)C(O)NH—, —NHC(O)N(R⁴)—, —C(O)O—,—OC(O)—, substituted or unsubstituted alkylene, unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, orsubstituted or unsubstituted heterocycloalkylene; R⁴ is independentlyhydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —C(O)R^(4A), —C(O)OR^(4A),—C(O)NR^(4A)R^(4B), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ isindependently:

wherein R¹³ is hydrogen, halogen, substituted or unsubstituted alkyl;and z13 is an integer from 0 to 3; each R^(1A), R^(1B), R^(1C), R^(1D),R^(3A), R^(3B), R^(4A), and R^(4B) is independently hydrogen, —CX₃, —CN,—COOH, —CONH₂, —CHX₂, —CH₂X, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(1A) and R^(1B) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; R^(3A) andR^(3B) substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; R^(4A) and R^(4B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; each X, X¹, X³, and X⁴ is independently —F,—Cl, —Br, or —I; n1 is independently an integer from 0 to 4; and m1 andv1 are independently 1 or
 2. 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: Ring A is indolinyl,indazolyl, benzimidazolyl, benzoxazolyl, azaindolyl, purinyl, indolyl,pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,benzofuranyl, benzothienyl,

R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B), —NHNR^(1A)R^(1B),—ONR^(1A)R^(1B), —NHC=(O)NHNR^(1A)R^(1B), —NHC(O)NR^(1A)R^(1B),N(O)_(m1), —NR^(1A)R^(1B), —C(O)R^(1C), —C(O)—OR^(1C),—C(O)NR^(1A)R^(1B), —OR^(1D), —NR^(1A)SO₂R^(1D), —NR^(1A)C(O)R^(1C),—NR^(1A)C(O)OR^(1C), —NR^(1A)OR^(1C), —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, or substituted orunsubstituted heterocycloalkyl; or two adjacent R¹ substituents mayoptionally be joined to form a substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; z1 is aninteger from 0 to 4; L³ is a bond, —S(O)₂—, —N(R³)—, —O—, —S—, —C(O)—,—C(O)N(R³)—, —N(R³)C(O)—, —N(R³)C(O)NH—, —NHC(O)N(R³)—, —C(O)O—,—OC(O)—, unsubstituted alkylene, unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedarylene, or unsubstituted heteroarylene; R³ is independently hydrogen,—CX³ ₃, —CHX³ ₂, —CH₂X³, —C(O)R^(3A), —C(O)OR^(3A), —C(O)NR^(3A)R^(3B),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; L⁴ is a bond, —S(O)₂—, —N(R⁴)—,—O—, —S—, —C(O)—, —C(O)N(R⁴)—, —N(R⁴)C(O)—, —N(R⁴)C(O)NH—,—NHC(O)N(R⁴)—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene,unsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, or substituted or unsubstituted heterocycloalkylene; R⁴is independently hydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —C(O)R^(4A),—C(O)OR^(4A), —C(O)NR^(4A)R^(4B), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; eachR^(1A), R^(1B), R^(1C), R^(1D), R^(3A), R^(3B), R^(4A), and R^(4B) isindependently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1A) and R^(1B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R^(3A) and R^(3B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R^(4A) and R^(4B) substituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; each X, X¹,X³, and X⁴ is independently —F, —Cl, —Br, or —I; n1 is independently aninteger from 0 to 4; and m1 and v1 are independently 1 or
 2. 3. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein: ring A is indolinyl, indazolyl, benzimidazolyl, benzoxazolyl,azaindolyl, purinyl, indolyl, pyrazinyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl,

R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B), —ONR^(1A)R^(1B), —N(O)_(m1),—NR^(1A)R^(1B), —OR^(1D), —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocycloalkyl; z1 is an integer from 0to 4; L³ is a bond or unsubstituted alkylene; L⁴ is a bond, —O—,—N(R⁴)—, or —C(O)—; R⁴ is hydrogen or substituted or unsubstitutedalkyl; R⁵ is independently:

wherein R¹³ is hydrogen, halogen, substituted or unsubstituted alkyl;and z13 is an integer from 0 to 3; each R^(1A), R^(1B), R^(1C), andR^(1D) is independently hydrogen, —CX₃, —CHX₂, —CH₂X, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; each Xand X¹ are independently —F, —Cl, —Br, or —I; n1 is independently aninteger from 0 to 4; and m1 and v1 are independently 1 or
 2. 4. Thecompound of claim 1, wherein the compound is of Formula (I), or apharmaceutically acceptable salt thereof, wherein: Ring A is phenyl; R¹is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN, —SO_(n1)R^(1D),−SO_(v1)NR^(1A)R^(1B), —NHNR^(1A)R^(1B), —ONR^(1A)R^(1B),—NHC=(O)NHNR^(1A)R^(1B), —NHC(O)NR^(1A)R^(1B), N(O)_(m1),—NR^(1A)R^(1B), —C(O)R^(1C), —C(O)—OR^(1C), —C(O)NR^(1A)R^(1B),—OR^(1D), —NR^(1A)SO₂R^(1D), —NR^(1A)C(O)R^(1C), —NR^(1A)C(O)OR^(1C),—NR^(1A)OR^(1C), —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocycloalkyl; or two adjacent R¹ substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; z1 is an integer from 0 to 4;L³ is a bond, —S(O)₂—, —N(R³)—, —O—, —S—, —C(O)—, —C(O)N(R³)—,—N(R³)C(O)—, —N(R³)C(O)NH—, —NHC(O)N(R³)—, —C(O)O—, —OC(O)—,unsubstituted alkylene, unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstituted arylene, orunsubstituted heteroarylene; R³ is independently hydrogen, —CX³ ₃, —CHX³₂, —CH₂X³, —C(O)R^(3A), —C(O)OR^(3A), —C(O)NR^(3A)R^(3B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; L⁴ is a bond, —S(O)₂—, —N(R⁴)—, —O—, —S—,—C(O)—, —C(O)N(R⁴)—, —N(R⁴)C(O)—, —N(R⁴)C(O)NH—, —NHC(O)N(R⁴)—, —C(O)O—,—OC(O)—, substituted or unsubstituted alkylene, unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, orsubstituted or unsubstituted heterocycloalkylene; R⁴ is independentlyhydrogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —C(O)R^(4A), —C(O)OR^(4A),—C(O)NR^(4A)R^(4B), substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; eachR^(1A), R^(1B), R^(1C), R^(1D), R^(3A), R^(3B), R^(4A), and R^(4B) isindependently hydrogen, —CX₃, —CN, —COOH, —CONH₂, —CHX₂, —CH₂X,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1A) and R^(1B) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R^(3A) and R^(3B) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R^(4A) and R^(4B) substituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; each X, X¹,X³, and X⁴ is independently —F, —Cl, —Br, or —I; n1 is independently aninteger from 0 to 4; and m1 and v1 are independently 1 or
 2. 5. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein: Ring A is phenyl; R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂,—CH₂X¹, —CN, —SO_(n1)R^(1D), —SO_(v1)NR^(1A)R^(1B), —ONR^(1A)R^(1B),—N(O)_(m1), —NR^(1A)R^(1B), —OR^(1D), —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl; z1 is aninteger from 0 to 4; L³ is a bond or unsubstituted alkylene; L⁴ is abond, —O—, —N(R⁴)—, or —C(O)—; R⁴ is hydrogen or substituted orunsubstituted alkyl; R⁵ is independently:

wherein R¹³ is hydrogen, halogen, substituted or unsubstituted alkyl;and z13 is an integer from 0 to 3; each R^(1A), R^(1B), R^(l)c andR^(1D) is independently hydrogen, —CX₃, —CHX₂, —CH₂X, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; each Xand X¹ are independently —F, —Cl, —Br, or —I; n1 is independently aninteger from 0 to 4; and m1 and v1 are independently 1 or
 2. 6. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein L² is —S(O)₂— or —C(O)NHCH₂—.
 7. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R¹ isindependently halogen, —OR^(1D), NR ^(1A)R^(1B), —CN, or substituted orunsubstituted alkyl, wherein each R^(1A), R^(1B), and R^(1D) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.
 8. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein each R¹ isindependently halogen, —CN, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCHX¹ ₂,—OCH₂X¹, —OR^(1D), or —NR^(1A)R^(1B), wherein each R^(1A), R^(1B), andR^(1D) is independently hydrogen, substituted or unsubstituted alkyl, orsubstituted or unsubstituted aryl.
 9. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁵ is:


10. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁵ is:

wherein R¹³ is hydrogen, halogen, substituted or unsubstituted alkyl;and z13 is an integer from 0 to
 3. 11. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein ring A is phenyl. 12.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein ring A is indolyl.
 13. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein L³ is unsubstitutedC₁-C₈ alkylene.
 14. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein L³ is unsubstituted methylene.
 15. Thecompound of claim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 17. A pharmaceuticalcomposition comprising the compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.18. A method of reducing the level of a K-Ras protein in a subject inneed thereof, comprising administering to the subject an effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof.
 19. A method of reducing the activity level of a K-Ras proteinin a subject in need thereof, comprising administering to the subject aneffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 20. A method for treating cancer in a subjectsuffering from said cancer, comprising administering to the subject atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof, wherein said cancer ispancreatic cancer, lung cancer, or colorectal cancer.